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Pathological transition as the arising mechanism for drug resistance in lung cancer

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Abstract

Despite the tremendous efforts for improving therapeutics of lung cancer patients, its prognosis remains disappointing. This can be largely attributed to the lack of comprehensive understanding of drug resistance leading to insufficient development of effective therapeutics in clinic. Based on the current progresses of lung cancer research, we classify drug resistance mechanisms into three different levels: molecular, cellular and pathological level. All these three levels have significantly contributed to the acquisition and evolution of drug resistance in clinic. Our understanding on drug resistance mechanisms has begun to change the way of clinical practice and improve patient prognosis. In this review, we focus on discussing the pathological changes linking to drug resistance as this has been largely overlooked in the past decades.

Background

Lung cancer can be classified into two main histological types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). They account for approximately 15% and 85% of all lung cancers, respectively [1]. NSCLC can be further divided into three subtypes, namely lung adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). These subtypes harbor different features, with distinct gene expression profiles [2] as well as lineage-specific biomarkers [3]. For example, lung ADC commonly express thyroid transcription factor-1 (TTF1, also known as NKX2-1) [4, 5], a p53-homologous nuclear protein mainly involved in basal cell commitment. LCC, as a pathologically heterogeneous entity which might represent solid ADC or non-keratinizing SCC, have no well-established biomarkers, yet [6]. In contrast to NSCLC, SCLC frequently express neuroendocrine markers, such as achaete-scute homologue 1 (ASCL1, also known as ASH1), neural cell adhesion molecule (NCAM) and synaptophysin (SYP) [7]. Lung ADC is frequently found at distal bronchioles [8], whereas SCC is often observed in more proximal airways [8]. Most lung ADC are considered as originating from alveolar type II (AT II) cells, club cells, or bronchial-alveolar stem cells (BASCs) [9], whereas SCC is observed at more proximal airway [6]. Most lung ADC are considered as originating from alveolar type II (AT II) cells, club cells, or bronchio-alveolar stem cells (BASCs) [7], whereas, lung SCC are mainly derived from basal cells located underneath trachea or bronchus epithelia [7]. SCLC arises from pulmonary neuro-endocrine (NE) cells and often spread along bronchi in a submucosal and circumferential fashion [8].

Despite of persistent medical efforts in last decades, lung cancer prognosis still remains disappointing, with a 5-year survival rate of approximately 15% [9]. This is in part attributed to the acquisition of early drug resistance. Understanding of drug resistance mechanisms hopefully improves therapeutic strategies and eventually changes clinical practice. We classify drug resistance mechanisms into three different levels: molecular, cellular and pathological level (Fig. 1). Although these three are closely linked with each other, changes in molecular level might occur in tumor initiation and development prior to those in the other two levels, which enable an early diagnosis with the usage of potential biomarkers. Previous studies have paid extensive attentions to the molecular and cellular level. In this review, we mainly focus on the pathological level which is largely unappreciated previously.

Fig. 1
figure1

Three different levels of drug resistance mechanisms in lung cancer. Drug resistance develops at three different levels: molecular, cellular, and pathological level. Molecular level mechanism includes secondary EGFR T790M and MET amplification after the relapse from EGFR-TKI therapy. Cellular level mechanism mainly involves CSC and EMT. Pathological level mechanism includes the ADC-to-SCC transition and ADC or SCC-to-SCLC transition. EGFR epidermal growth factor receptor, EGFR-TKI epidermal growth factor receptor-tyrosine kinase inhibitor, BRAF serine/threonine-protein kinase B-raf, HER2 receptor tyrosine-protein kinase erbB-2, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, MET hepatocyte growth factor receptor, EMT epithelial-to-mesenchymal transition, CSC cell stem cell, ADC adenocarcinoma, SCC squamous cell carcinoma, SCLC small cell lung cancer

Drug resistance mechanisms at molecular and cellular level

Molecular changes are frequently detected in relapsed patients after clinical treatment including chemotherapy, targeted therapy and immunotherapy. There are multiple drug resistance mechanisms at molecular level limit the effectiveness of chemotherapy, e.g., the deregulation of genes involved in drug uptake, cell cycle, apoptosis, sphingolipid metabolism as well as intracellular drug sequestration [10]. Gardner et al. [11] recently show that the down-regulation of Schlafen 11 (SLFN 11) mediated by enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and H3K27me3 modification induces DNA damage repair and thus enables SCLC chemo-resistance. Molecular alterations are also observed in relapsed patients after targeted therapy in lung cancers [12]. For example, during epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment, secondary EGFR mutation T790M, MET proto-oncogene, receptor tyrosine kinase (MET, also known as hepatocyte growth factor receptor, HGFR) amplification, receptor tyrosine-protein kinase erbB-2 (ERBB2, also known as HER2) amplification as well as Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are often detectable in relapsed lung cancer patients and known to contribute to drug resistance [13,14,15]. In the case of anaplastic lymphoma kinase (ALK)-rearranged NSCLC patients, ALK point mutations, KIT proto-oncogene receptor tyrosine kinase amplification, and other driver mutations are implicated for disease relapse [13]. During the immune checkpoint blockade treatment, neo-antigen landscape shows dynamic change which contributes to the resistance to immunotherapy [16]. These data together support an important role of molecular alterations in orchestrating drug resistance.

Drug resistance mechanisms at cellular level is mainly classified into two types: cancer stem cell (CSC)- and epithelial-to-mesenchymal transition (EMT)-mediated drug resistance. CSCs are considered to be highly plastic, resistant to chemotherapy and capable to seed new aggressive and chemo-resistant tumors in distant organs [17]. Great efforts have been paid to investigate the vulnerability of CSC with the purpose to overcome drug resistance. However, the findings of reversible transition between CSC and non-CSC make the specific targeting of CSC extremely difficult [17]. The non-CSC, frequently as the major component of malignant tumors, is also known to harbor strong stemness and plasticity [18]. Such stemness and plasticity allows non-CSC to de-differentiate into CSC under stressful environment [18, 19]. Such de-differentiation together with the reversible transition between CSC and non-CSC creates a huge hurdle for effective targeting either CSC or non-CSC alone [19].

The transition from epithelial cells to mesenchymal cells also reflects the strong plasticity of cancer cells, which is frequently implicated in drug resistance. In contrast to epithelial cells, mesenchymal cells tend to harbor strong transforming growth factor beta (TGFβ) and Wnt autocrine signaling [20]. The EMT often associates with down-regulation of multiple apoptotic signaling pathways, while it enhances drug efflux and slows cell proliferation [17]. The EMT activates several processes including of programmed death-ligand 1 (PD-L1) expression elevation and tumor suppressor region 1 (TSP-1) secretion elevation, which induces immune suppression and promotes immune escape [17, 21]. Besides, several transcription factors including snail family transcriptional repressor (SNAIL), twist family bHLH transcription factor (TWIST) and zinc finger E-box binding homeobox 1 (ZEB1) activate classical EMT-associated properties and induce anti-apoptotic and pro-survival phenotype supporting malignant progression [22]. All these EMT-associated features collectively promote cancer cell survival and help them escape from effective drug treatment. However, this doesn’t always turn out to be true. A recent study shows that EMT triggered by EGFR-TKI treatment associates with decreased PD-L1 expression, indicative of the complexity of the link between EMT and immune checkpoint regulation [23].

Drug resistance mechanisms at pathological level

Pathological transition has recently been implicated in clinic. Observation of lung ADC transition to either SCC or SCLC has been reported in relapsed patients [24, 25]. Below we summarized the current progress and discuss their link to drug resistance (Fig. 2).

Fig. 2
figure2

Pathological transition of different lung cancer subtypes. Lung cancer can be divided into two subtypes: NSCLC and SCLC. NSCLC can be further divided into three subtypes: ADC, SCC, and LCC. ADCs are considered to originate from alveolar type II cells, club cells or BASCs. SCC frequently found at more proximal airways is presumably derived from basal cells. SCLC is typically derived from neuroendocrine cells. Pathological transition is observed in clinic including lung ADC-to-SCC transdifferentiation and ADC or SCC-to-SCLC transition. Loss of LKB1 or RB1 potentially contributes to the squamous and SCLC transition, respectively. NSCLC non-small cell lung cancer, SCLC small cell lung cancer, ADC adenocarcinoma, SCC squamous cell carcinoma, LCC large cell carcinoma, BASC bronchio-alveolar stem cell, LKB1 liver kinase B1, RB1 retinoblastoma

ADC/SCC-to-SCLC transition promotes drug resistance

Two large cohort studies reveal that approximately 5% human lung cancer display the mixed pathology such as adenosquamous carcinoma (Ad-SCC), combined large cell neuroendocrine carcinoma (LCNEC) and combined SCLC [26, 27]. Combined SCLC accounts for about 2.2% of all lung cancer [28]. Previous studies show that the SCLC and non-SCLC components of combined SCLC often share exactly the same genetic mutations [29, 30], indicating that these two different pathological lesions might share the same cells of origin and/or exist potential pathological transition. Notably, most of these pathologically mixed cancer are observed at advanced stages [26, 27], indicating that the potential pathological transition might occur during late stage of malignancy progression.

The SCLC transition is also observed in clinic after patient relapse from molecular targeted therapy. This is initially found in a woman with lung adenocarcinoma [31]. First biopsy shows that her tumor harbors EGFR exon 19 deletion and erlotinib treatment shows partial response. After 18 months of treatment, the tumor mass progresses. The second biopsy is then performed and shows SCLC pathology with the original EGFR exon 19 deletion, indicative of the potential transition from ADC to SCLC and its link to drug resistance. In later studies, researchers provided solid evidence showing that the transition of EGFR-mutant ADC to SCLC serves as a drug resistance mechanism. Sequist et al. [32] find that about 14% (5/37 cases) drug-resistant ADC cases transit to SCLC and thereby the standard SCLC therapy overcomes such resistance. We summarized the SCLC transition cases with available clinical details in Table 1. Among the total 33 cases, there are 14 males and 19 females. Despite of those unknown smoking status, about 77% (20/26) of the patients are non-smokers. There seems no preference for gender and smoking status. Except for 8 cases with unknown mutation status, most patients (96%, 24/25) show exactly the same oncogenic EGFR mutations or ALK fusions in the first and second biopsies. Additional mutations such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, EGFR T790M are also detectable after relapse in 1 and 2 cases, respectively, indicative of the combined mechanisms at both molecular and pathological levels [13].

Table 1 Characteristics of 33 relapsed lung ADC patients with SCLC transition

Transition from ADC to SCLC is also observed in patients with ALK rearrangement. Two relapsed patients with ALK fusion after receiving alectinib or crizotinib treatment showed ADC-to-SCLC transition [33, 34]. Another patient with wild-type EGFR also showed the transition to SCLC after developing TKI resistance [35]. These data indicate that the transition to SCLC might be independent of various oncogenic drivers.

The transition from SCC to SCLC is also associated with drug resistance in the clinic [28]. After receiving surgery or radiation and chemotherapy, a total of 16 SCC patients were found to have SCLC transition. The majority of transited SCLC (12/16, 75%) is found to locate at the same sites as the primary tumors.

Recent studies have begun to uncover the underlying mechanisms involved in the ADC-to-SCLC transition [25, 36]. Niederst et al. [25] found that retinoblastoma (RB) was universally lost in all transited SCLC. This is consistent with previous finding about the concurrent loss of RB and p53 alleles in most SCLC [37]. Consistently, Owen et al. [38] find that both RB and P53 deficiencies are required to reprogram lung epithelial cells to SCLC. Despite of the genomic evidence of EGFR mutations in transited SCLC, the expression of EGFR mutants are found to be remarkably decreased or even shut off [25]. Whether RB loss contributes to such down-regulation of EGFR level remains unknown. However, the decreased EGFR expression provides a reasonable explanation for the TKI resistance in transited SCLC [36].

Lung ADC-to-SCC transition links to drug resistance

Lung Ad-SCC is the major subtype of pathologically mixed lung cancer. Ad-SCC contains both adenomatous and squamous pathology [39] and accounts for approximately 60%–75% of all mixed lung cancer [26, 27]. Similar to combined SCLC, the adenomatous and squamous components in Ad-SCC frequently share the same genetic alterations [40,41,42,43], indicative of potential pathological transition. Up to date, about 22 reported cases support the link between the ADC-to-SCC transition (AST) and drug resistance (Table 2). Among these patients, the majority (81.8%) is female and 12 (66.7%) of them are non-smoker. Almost all of the transited SCC displays the same EGFR mutations as detected in ADC. EGFR T790M and PIK3CA mutations were also detected in 4 (18.2%) patients, indicative of complicate resistance mechanisms. Moreover, 2 ALK-fusion patients showed AST after the relapse from molecular targeted therapy. AST were also detected in two patients with wild-type EGFR. Except for molecular targeted therapy, AST was also found in patients treated with chemotherapy or immunotherapy. Two patients received chemotherapy and one received chemotherapy and immunotherapy were found to have SCC transition at relapse. These data convincingly support the important link between AST and drug resistance.

Table 2 Characteristics of 22 relapsed lung ADC patients with potential squamous transition

Evidence from animal models supporting the ADC-to-SCC transition

Studies of the Genetically Engineered Mouse Models (GEMMs) have provided strong in vivo evidence in supporting the ADC-to-SCC transition [44, 45]. We and others have previously found that liver kinase B1 (LKB1, also named as STK11) is frequently mutated in human lung ADC, SCC as well as Ad-SCC [46, 47]. Inactivating mutations of LKB1 seem to be significantly concurrent with Kras mutations and confers lung ADC with strong malignant potential and promotes metastasis [46, 48]. Strikingly, Lkb1 deletion in KrasG12D GEMMs could make ADC progressively transition into SCC via metabolic reprogramming and excessive accumulation of reactive oxygen species (ROS) [49]. YAP, the major transcriptional co-factor of the Hippo pathway, functions as the barrier for AST. When Lkb1 is lost in lung ADC, YAP is activated and up-regulates ZEB2 expression, which in turn represses DNp63 transcription. During the malignant progression and when ADC grows big, the deficiency of extracellular matrix (ECM), e.g., decreased collagen deposition, fails to promote YAP activation and thus relieves ZEB2-mediated repression of DNp63 expression and eventually triggers the AST program [50].

The lysyl oxidase (LOX) family are responsible for cross-linking collagen and elastin, and thus importantly maintain the rigidity and structural stability of ECM [51]. The LOX family has five members including LOX, LOXL1, LOXL2, LOXL3 and LOXL4 with similar catalytic activities [51]. Previous study shows that LOX importantly regulates AST through ECM remodeling [44, 49]. During the AST process, LOX decreases with concurrent reduction of collagen disposition [44]. Pharmacological inhibition of LOX significantly accelerates the AST process in KrasG12D/Lkb1L/L (KL) model [44]. More importantly, long-term LOX inhibition could trigger AST even in KrasG12D/Trp53L/L (KP) mouse model, which is known to produce lung ADC only [52]. This highlights an essential role of LOX and ECM remodeling in AST, which is independent of LKB1 deficiency [52]. The transited SCC show strong resistance to LOX inhibition in contrast to lung ADC, consistent with the association of AST and drug resistance [52].

Chromatin analysis reveals the contribution of epigenetic regulation to AST process in KL model. The transited SCC are featured with the decrease of H3K27me3 level and the increase of H3K27ac and H3K4me3 levels, which might be involved in regulating several key squamous-associated genes such as Sox2, ∆Np63 and Ngfr [45]. EZH2, the methyltransferase responsible for catalyzing H3K27me3 [53], is highly expressed in transited SCC. Similar findings are observed in human lung SCC and the squamous component of human Ad-SCC [45].

Interestingly, Lkb1 loss together with ectopic SOX2 expression promotes the development of SCC, potentially through the progressive transition from ADC to SCC [54]. Simultaneous deletion of FoxA1/2 and Nkx2-1 in KRAS mouse model promotes the transition from ADC to SCC and these tumors are somehow different from those in KL model, and featured with keratinizing squamous cell carcinomas [55]. It remains interesting to see whether LKB1 is inactivated in this model and the squamous transition links to drug resistance.

Previous work has demonstrated that BASCs and club cells are the main cell types for squamous transition [45]. Up to date, most techniques used to isolate BASCs are based on FACS sorting. We recently take advantage of dual recombinant systems including Cre/LoxP and Dre/Rox systems to do the specific lineage-tracing of BASCs in vivo [56]. We found that BASCs are capable of differentiating into multiple cell lineages including club cells, ciliated cells, alveolar type I and type II cells in various lung injury models [56]. Future work will be interesting to illustrate whether BASC-derived tumors are prone to transdifferentiate into SCC when Lkb1 is deleted.

Conclusion

The drug resistance mechanisms can be classified into three different levels: molecular, cellular and pathological level. The ADC-to-SCLC transition and ADC-to-SCC transition are two major patterns for pathological transition in link to acquired drug resistance. A better understanding of drug resistance mechanisms will hopefully change the way of clinical practice and improve patient prognosis.

Perspectives

It’s well established that the pathology of lung cancer serves as an important factor for clinical management, e.g., lung ADC, SCC and SCLC are therapeutically treated differently. The link between pathological transition and drug resistance indicates that even in the era of targeted therapy, the importance of pathology should not be neglected. For example, in EGFR-mutant lung ADC, the median progression-free survival (PFS) after TKI treatment is about 10–13 months [57]. In contrast, the PFS for lung SCC with similar EGFR mutations is only 2.4 months [57]. Even more dramatic finding is that transited SCLC from EGFR-mutant ADC have almost no response to TKI, potentially due to the shut-down of EGFR transcription [36]. This could be explained by the ‘missing target’ theory, in which the therapeutic target disappears after long-term treatment and drug resistance development. It will be interesting to test how EGFR mutants are epigenetically regulated and how we could transcriptionally re-activate EGFR mutants, which might help develop novel therapeutic strategies to overcome drug resistance in these transited SCLC.

Recent studies have also indicated that therapeutic targets could “face off” between different pathologies, e.g., YAP works as proto-oncogene in lung ADC but tumor suppressor in SCC. In human lung ADC, YAP is highly expressed and associated with poor prognosis [58]. Consistently, ectopic YAP expression accelerates lung ADC progression in KrasG12D mouse model [59]. In contrast, YAP suppresses lung SCC progression potentially through down-regulation of the lineage-survival gene DNP63 [60]. We find that digitoxin is highly potent in suppressing SCC growth through YAP activation [60]. Understanding of the double faces of YAP in lung ADC and SCC will certainly help gain novel insights into the process of AST and pathological transition.

Interestingly, pathological transition is not limited to AST or ADC/SCC-to-SCLC transition. Although rare, one case report shows the transition of EGFR-mutated ADC to both SCC and SCLC [61]. Pathological transition is also observed when comparing the primary tumor with brain metastases [62]. For example, two patients with primary lung ADC show SCC or SCLC in brain metastasis whereas another patient with primary lung SCC shows ADC in brain metastasis. Transitions from ADC to LCNEC, or Ad-SCC to SCLC have also been reported [63, 64]. Obviously, our understanding of pathological transition is still very limited. Most case reports are from the EGFR-mutant lung cancer patients who are ethically treated with multiple biopsies. With the improvement of treatment strategies, multiple biopsies specimens will hopefully provide more insightful information about pathological transition.

Besides lung cancer, mixed pathologies are also observed in other types of cancer (Fig. 3), e.g., Ad-SCC are detectable in human colon cancer [65], prostate cancer [66,67,68,69,70,71,72,73,74,75,76] and pancreatic cancer [77]. The AST or AST-like process has been previously reported in pancreatic cancer [78], thyroid gland carcinoma [79,80,81] as well as gastric cancer [82]. Moreover, neuroendocrine differentiation in ADC has been reported in prostate cancer. After androgen receptor (AR) treatment in castration-resistant prostate cancer (CPRC), certain patients develop neuroendocrine small cell cancer (CRPC-NE) [83,84,85]. It is understandable that the malignant transformation of benign tumors induce drug resistance [86]. Interestingly, malignant tumors may sometimes become less aggressive or even benign after chemotherapy, such as neuroblastoma to ganglioneuroma transition [87] and malignant germ cell tumors to teratoma transition [88,89,90]. These transformed tumors are still growing but show the resistance to chemotherapy.

Fig. 3
figure3

Pathological transition of different types of cancers. Pathological transition in lung cancer includes AST and ADC or SCC-to-SCLC transition. The AST or AST-like process is previously reported in thyroid gland carcinoma, pancreatic cancer as well as gastric cancer. Moreover, neuroendocrine differentiation in ADC has also been reported in prostate cancer. T thyroid gland, L lung, S stomach, Pa pancreas, Pr prostate, Pro proliferation, SCLC small cell lung cancer, ADC adenocarcinoma, SCC squamous cell carcinoma, AST ADC to SCC transition, CPRC castration-resistant prostate cancer, NE neuroendocrine

Together, these findings suggest that pathological transition might be more common than we previously thought. No doubt, the better understanding of pathological transition and the link with drug resistance will be beneficial for future clinic practice and eventually help cancer patients.

Availability of data and materials

The datasets generated and/or analyzed during the current study are available in the Pubmed repository. For Table 1, we used one or a combination of the following terms in PubMed and selected articles on the basis of relevance to transition from ADC to SCLC: ‘non-small cell lung cancer’, ‘transition’, ‘transformation’, ‘transdifferentiation’, ‘adenocarcinoma’, ‘small cell carcinoma’ and ‘small cell lung cancer’. All dates and languages are included in the search. We only collect case reports with detailed clinical information. For Table 2, we used one or a combination of the following terms in PubMed and selected articles on the basis of relevance to transformation from ADC to SCC: ‘transition’, ‘transformation’, ‘transdifferentiation’, ‘adenocarcinoma’ and ‘squamous cell carcinoma’. All dates and languages are included in the search. We only collect case reports with detailed clinical information.

Abbreviations

SCLC:

small cell lung cancer

NSCLC:

non-small cell lung cancer

ADC:

adenocarcinoma

SCC:

squamous cell carcinoma

LCC:

large cell carcinoma

TTF1:

thyroid transcription factor-1

DNP63:

delta N tumor protein 63

ASCL1:

achaete-scute homologue 1

NCAM:

neural cell adhesion molecule

SYP:

synaptophysin

AT II:

alveolar type II

BASC:

bronchio-alveolar stem cell

NE:

neuro-endocrine

SLFN 11:

schlafen 11

EZH2:

enhancer of zeste 2 polycomb repressive complex 2 subunit

EGFR:

epidermal growth factor receptor

MET:

MET proto-oncogene, receptor tyrosine kinase (also known as HGFR)

HGFR:

hepatocyte growth factor receptor

ERBB2:

receptor tyrosine-protein kinase erbB-2 (also known as HER2)

KRAS:

kirsten rat sarcoma viral oncogene homolog

ALK:

anaplastic lymphoma kinase

KIT:

KIT proto-oncogene receptor tyrosine kinase

TGFβ:

transforming growth factor beta

EMT:

epithelial-to-mesenchymal transition

PD-L1:

programmed death-ligand 1

TSP-1:

tumor suppressor region 1

SNAIL:

snail family transcriptional repressor

TWIST:

wist family bHLH transcription factor

ZEB1:

zinc finger E-box binding homeobox 1

Ad-SCC:

adenosquamous carcinoma

LCNEC:

large cell neuroendocrine carcinoma

RB:

retinoblastoma

AST:

ADC-to-SCC transition

GEMM:

Genetically Engineered Mouse Model

LKB1:

liver kinase B1

ROS:

reactive oxygen species

ECM:

extracellular matrix

LOX:

lysyl oxidase

KL:

KrasG12D/Lkb1L/L

KP:

KrasG12D/Trp53L/L

PFS:

progression-free survival

EGFR-TKI:

EGFR-tyrosine kinase inhibitor

CSC:

cancer stem cell

AR:

androgen receptor

CPRC:

castration-resistant prostate cancer

CRPC-NE:

neuroendocrine small cell cancer

References

  1. 1.

    Testa U, Castelli G, Pelosi E. Lung cancers: molecular characterization, clonal heterogeneity and evolution, and cancer stem cells. Cancers. 2018. https://doi.org/10.3390/cancers10080248.

  2. 2.

    Fujii T, Dracheva T, Player A, Chacko S, Clifford R, Strausberg RL, et al. A preliminary transcriptome map of non-small cell lung cancer. Can Res. 2002;62(12):3340.

  3. 3.

    Rekhtman N, Ang DC, Sima CS, Travis WD, Moreira AL. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol. 2011;24:1348. https://doi.org/10.1038/modpathol.2011.92.

  4. 4.

    Righi L, Graziano P, Fornari A, Rossi G, Barbareschi M, Cavazza A, et al. Immunohistochemical subtyping of nonsmall cell lung cancer not otherwise specified in fine-needle aspiration cytology: a retrospective study of 103 cases with surgical correlation. Cancer. 2011;117(15):3416–23. https://doi.org/10.1002/cncr.25830.

  5. 5.

    Barlesi F, Pinot D, Legoffic A, Doddoli C, Chetaille B, Torre JP, et al. Positive thyroid transcription factor 1 staining strongly correlates with survival of patients with adenocarcinoma of the lung. Br J Cancer. 2005;93(4):450–2. https://doi.org/10.1038/sj.bjc.6602717.

  6. 6.

    Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 2014;14(8):535–46. https://doi.org/10.1038/nrc3775.

  7. 7.

    Hanna JM, Onaitis MW. Cell of origin of lung cancer. J Carcinog. 2013;12:6. https://doi.org/10.4103/1477-3163.109033.

  8. 8.

    Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer. 2017;17(12):725–37. https://doi.org/10.1038/nrc.2017.87.

  9. 9.

    Edwards BK, Noone A-M, Mariotto AB, Simard EP, Boscoe FP, Henley SJ, et al. Annual report to the nation on the status of cancer, 1975–2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer. 2014;120(9):1290–314. https://doi.org/10.1002/cncr.28509.

  10. 10.

    Kartal-Yandim M, Adan-Gokbulut A, Baran Y. Molecular mechanisms of drug resistance and its reversal in cancer. Crit Rev Biotechnol. 2016;36(4):716–26. https://doi.org/10.3109/07388551.2015.1015957.

  11. 11.

    Gardner EE, Lok BH, Schneeberger VE, Desmeules P, Miles LA, Arnold PK, et al. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis. Cancer Cell. 2017;31(2):286–99. https://doi.org/10.1016/j.ccell.2017.01.006.

  12. 12.

    Zhang J, Tian C, Lv F, Wang J, Han W, Nie J, et al. Molecular analysis of cell-free DNA identifies distinct molecular features in patients with chemosensitive and chemorefractory small cell lung cancer. Cancer Commun (London, England). 2019;39(1):20. https://doi.org/10.1186/s40880-019-0363-y.

  13. 13.

    Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014;11(8):473–81. https://doi.org/10.1038/nrclinonc.2014.104.

  14. 14.

    Zhang S, Zhu L, Xia B, Chen E, Zhao Q, Zhang X, et al. Epidermal growth factor receptor (EGFR) T790M mutation identified in plasma indicates failure sites and predicts clinical prognosis in non-small cell lung cancer progression during first-generation tyrosine kinase inhibitor therapy: a prospective observational study. Cancer Commun (London, England). 2018;38(1):28. https://doi.org/10.1186/s40880-018-0303-2.

  15. 15.

    Wang F, Diao XY, Zhang X, Shao Q, Feng YF, An X, et al. Identification of genetic alterations associated with primary resistance to EGFR-TKIs in advanced non-small-cell lung cancer patients with EGFR sensitive mutations. Cancer Commun (London, England). 2019;39(1):7. https://doi.org/10.1186/s40880-019-0354-z.

  16. 16.

    Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, White J, et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 2017;7(3):264–76. https://doi.org/10.1158/2159-8290.CD-16-0828.

  17. 17.

    Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14(10):611–29. https://doi.org/10.1038/nrclinonc.2017.44.

  18. 18.

    Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23(10):1124–34. https://doi.org/10.1038/nm.4409.

  19. 19.

    Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells—what challenges do they pose? Nat Rev Drug Discov. 2014;13(7):497–512. https://doi.org/10.1038/nrd4253.

  20. 20.

    Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011;145(6):926–40. https://doi.org/10.1016/j.cell.2011.04.029.

  21. 21.

    Larsen TV, Hussmann D, Nielsen AL. PD-L1 and PD-L2 expression correlated genes in non-small-cell lung cancer. Cancer Commun (London, England). 2019;39(1):30. https://doi.org/10.1186/s40880-019-0376-6.

  22. 22.

    Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18(2):128–34. https://doi.org/10.1038/nrc.2017.118.

  23. 23.

    Suda K, Rozeboom L, Rivard CJ, Yu H, Ellison K, Melnick MAC, et al. Therapy-induced E-cadherin downregulation alters expression of programmed death ligand-1 in lung cancer cells. Lung Cancer (Amsterdam, Netherlands). 2017;109:1–8. https://doi.org/10.1016/j.lungcan.2017.04.010.

  24. 24.

    Hou S, Han X, Ji H. Squamous transition of lung adenocarcinoma and drug resistance. Trends Cancer. 2016;2(9):463–6. https://doi.org/10.1016/j.trecan.2016.08.002.

  25. 25.

    Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun. 2015;6:6377. https://doi.org/10.1038/ncomms7377.

  26. 26.

    Deng P, Hu C, Zhou L, Li Y, Huang L. Clinical characteristics and prognostic significance of 92 cases of patients with primary mixed-histology lung cancer. Mol Clin Oncol. 2013;1(5):863–8. https://doi.org/10.3892/mco.2013.137.

  27. 27.

    Ruffini E, Rena O, Oliaro A, Filosso PL, Bongiovanni M, Arslanian A, et al. Lung tumors with mixed histologic pattern. Clinico-pathologic characteristics and prognostic significance. Eur J Cardiothorac Surg. 2002;22(5):701–7.

  28. 28.

    Ahmed T, Vial MR, Ost D, Stewart J, Hasan MA, Grosu HB. Non-small cell lung cancer transdifferentiation into small cell lung cancer: a case series. Lung Cancer (Amsterdam, Netherlands). 2018;122:220–3. https://doi.org/10.1016/j.lungcan.2018.06.024.

  29. 29.

    Wagner PL, Kitabayashi N, Chen YT, Saqi A. Combined small cell lung carcinomas: genotypic and immunophenotypic analysis of the separate morphologic components. Am J Clin Pathol. 2009;131(3):376–82. https://doi.org/10.1309/ajcpynpfl56pozqy.

  30. 30.

    Siegele BJ, Shilo K, Chao BH, Carbone D, Zhao W, Ioffe O, et al. Epidermal growth factor receptor (EGFR) mutations in small cell lung cancers: two cases and a review of the literature. Lung Cancer (Amsterdam, Netherlands). 2016;95:65–72. https://doi.org/10.1016/j.lungcan.2016.02.012.

  31. 31.

    Zakowski MF, Ladanyi M, Kris MG. EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med. 2006;355(2):213–5. https://doi.org/10.1056/NEJMc053610.

  32. 32.

    Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26. https://doi.org/10.1126/scitranslmed.3002003.

  33. 33.

    Cha YJ, Cho BC, Kim HR, Lee H-J, Shim HS. A case of ALK-rearranged adenocarcinoma with small cell carcinoma-like transformation and resistance to crizotinib. J Thorac Oncol. 2016;11(5):e55–8. https://doi.org/10.1016/j.jtho.2015.12.097.

  34. 34.

    Fujita S, Masago K, Katakami N, Yatabe Y. Transformation to SCLC after treatment with the ALK inhibitor alectinib. J Thorac Oncol. 2016;11(6):e67–72. https://doi.org/10.1016/j.jtho.2015.12.105.

  35. 35.

    Araki J, Okamoto I, Suto R, Ichikawa Y, Sasaki J. Efficacy of the tyrosine kinase inhibitor gefitinib in a patient with metastatic small cell lung cancer. Lung cancer (Amsterdam, Netherlands). 2005;48(1):141–4. https://doi.org/10.1016/j.lungcan.2004.10.012.

  36. 36.

    Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 2015;16(4):e165–72. https://doi.org/10.1016/s1470-2045(14)71180-5.

  37. 37.

    George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47–53. https://doi.org/10.1038/nature14664.

  38. 38.

    Park JW, Lee JK, Sheu KM, Wang L, Balanis NG, Nguyen K, et al. Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage. Science. 2018;362(6410):91. https://doi.org/10.1126/science.aat5749.

  39. 39.

    Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed. Lyon: International Agency for Research on Cancer; 2015. p. 7.

  40. 40.

    Niho S, Yokose T, Kodama T, Nishiwaki Y, Mukai K. Clonal analysis of adenosquamous carcinoma of the lung. Jpn J Cancer Res. 1999;90(11):1244–7. https://doi.org/10.1111/j.1349-7006.1999.tb00703.x.

  41. 41.

    Kang SM, Kang HJ, Shin JH, Kim H, Shin DH, Kim SK, et al. Identical epidermal growth factor receptor mutations in adenocarcinomatous and squamous cell carcinomatous components of adenosquamous carcinoma of the lung. Cancer. 2007;109(3):581–7. https://doi.org/10.1002/cncr.22413.

  42. 42.

    Jia X-L, Chen G. EGFR and KRAS mutations in Chinese patients with adenosquamous carcinoma of the lung. Lung Cancer (Amsterdam, Netherlands). 2011;74(3):396–400. https://doi.org/10.1016/j.lungcan.2011.04.005.

  43. 43.

    Tochigi N, Dacic S, Nikiforova M, Cieply KM, Yousem SA. Adenosquamous carcinoma of the lung: a microdissection study of KRAS and EGFR mutational and amplification status in a western patient population. Am J Clin Pathol. 2011;135(5):783–9. https://doi.org/10.1309/AJCP08IQZAOGYLFL.

  44. 44.

    Han X, Li F, Fang Z, Gao Y, Li F, Fang R, et al. Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma. Nat Commun. 2014;5:3261. https://doi.org/10.1038/ncomms4261.

  45. 45.

    Zhang H, Fillmore Brainson C, Koyama S, Redig AJ, Chen T, Li S, et al. Lkb1 inactivation drives lung cancer lineage switching governed by polycomb repressive complex 2. Nat Commun. 2017;8:14922. https://doi.org/10.1038/ncomms14922.

  46. 46.

    Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, et al. LKB1 modulates lung cancer differentiation and metastasis. Nature. 2007;448:807. https://doi.org/10.1038/nature06030.

  47. 47.

    Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 2002;62(13):3659–62.

  48. 48.

    Gao Y, Xiao Q, Ma H, Li L, Liu J, Feng Y, et al. LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc Natl Acad Sci USA. 2010;107(44):18892–7. https://doi.org/10.1073/pnas.1004952107.

  49. 49.

    Li F, Han X, Li F, Wang R, Wang H, Gao Y, et al. LKB1 inactivation elicits a redox imbalance to modulate non-small cell lung cancer plasticity and therapeutic response. Cancer Cell. 2015;27(5):698–711. https://doi.org/10.1016/j.ccell.2015.04.001.

  50. 50.

    Gao Y, Zhang W, Han X, Li F, Wang X, Wang R, et al. YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression. Nat Commun. 2014;5:4629. https://doi.org/10.1038/ncomms5629.

  51. 51.

    Wang T-H, Hsia S-M, Shieh T-M. Lysyl oxidase and the tumor microenvironment. Int J Mol Sci. 2016;18(1):62. https://doi.org/10.3390/ijms18010062.

  52. 52.

    Yao S, Han X, Tong X, Li F, Qin Z, Huang H-Y, et al. Lysyl oxidase inhibition drives the transdifferentiation from lung adenocarcinoma to squamous cell carcinoma in mice. bioRxiv. 2018. https://doi.org/10.1101/314393.

  53. 53.

    Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, et al. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell. 2008;32(4):491–502. https://doi.org/10.1016/j.molcel.2008.10.016.

  54. 54.

    Mukhopadhyay A, Berrett KC, Kc U, Clair PM, Pop SM, Carr SR, et al. Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Rep. 2014;8(1):40–9. https://doi.org/10.1016/j.celrep.2014.05.036.

  55. 55.

    Camolotto SA, Pattabiraman S, Mosbruger TL, Jones A, Belova VK, Orstad G, et al. FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer. eLife. 2018. https://doi.org/10.7554/elife.38579.

  56. 56.

    Liu Q, Liu K, Cui G, Huang X, Yao S, Guo W, et al. Lung regeneration by multipotent stem cells residing at the bronchioalveolar-duct junction. Nat Genet. 2019;51(4):728–38. https://doi.org/10.1038/s41588-019-0346-6.

  57. 57.

    Wang Z, Shen Z, Li Z, Duan J, Fu S, Liu Z, et al. Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations. Proc Natl Acad Sci USA. 2015;112(32):9990–5. https://doi.org/10.1073/pnas.1510837112.

  58. 58.

    Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X. Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci. 2010;101(5):1279–85. https://doi.org/10.1111/j.1349-7006.2010.01511.x.

  59. 59.

    Zhang W, Gao Y, Li F, Tong X, Ren Y, Han X, et al. YAP promotes malignant progression of Lkb1-deficient lung adenocarcinoma through downstream regulation of survivin. Cancer Res. 2015;75(21):4450–7. https://doi.org/10.1158/0008-5472.CAN-14-3396.

  60. 60.

    Huang H, Zhang W, Pan Y, Gao Y, Deng L, Li F, et al. YAP suppresses lung squamous cell carcinoma progression via deregulation of the DNp63-GPX2 axis and ROS accumulation. Cancer Res. 2017;77(21):5769–81. https://doi.org/10.1158/0008-5472.CAN-17-0449.

  61. 61.

    Yao Y, Zhu Z, Wu Y, Chai Y. Histologic transformation from adenocarcinoma to both small cell lung cancer and squamous cell carcinoma after treatment with gefitinib: a case report. Medicine. 2018;97(18):e0650. https://doi.org/10.1097/md.0000000000010650.

  62. 62.

    Jiang M, Zhu X, Han X, Jing H, Han T, Li Q, et al. Histologic transformation of non-small-cell lung cancer in brain metastases. Int J Clin Oncol. 2019;24(4):375–84. https://doi.org/10.1007/s10147-018-1369-1.

  63. 63.

    Kogo M, Shimizu R, Uehara K, Takahashi Y, Kokubo M, Imai Y, et al. Transformation to large cell neuroendocrine carcinoma as acquired resistance mechanism of EGFR tyrosine kinase inhibitor. Lung Cancer (Amsterdam, Netherlands). 2015;90(2):364–8. https://doi.org/10.1016/j.lungcan.2015.09.002.

  64. 64.

    Moriya R, Hokari S, Shibata S, Koizumi T, Tetsuka T, Ito K, et al. Histological transformation to large cell neuroendocrine carcinoma from lung adenocarcinoma harboring an EGFR mutation: an autopsy case report. Intern Med. 2017;56(15):2013–7. https://doi.org/10.2169/internalmedicine.56.7452.

  65. 65.

    Kang DB, Oh JT, Jo HJ, Park WC. Primary adenosquamous carcinoma of the colon. J Korean Surg Soc. 2011;80(Suppl 1):S31–5. https://doi.org/10.4174/jkss.2011.80.Suppl1.S31.

  66. 66.

    Bassler TJ Jr, Orozco R, Bassler IC, Boyle LM, Bormes T. Adenosquamous carcinoma of the prostate: case report with DNA analysis, immunohistochemistry, and literature review. Urology. 1999;53(4):832–4.

  67. 67.

    Baydar DE, Kosemehmetoglu K, Akdogan B, Ozen H. Prostatic adenosquamous carcinoma metastasizing to testis. Sci World J. 2006;6:2491–4. https://doi.org/10.1100/tsw.2006.388.

  68. 68.

    Gattuso P, Carson HJ, Candel A, Castelli MJ. Adenosquamous carcinoma of the prostate. Hum Pathol. 1995;26(1):123–6.

  69. 69.

    Accetta PA, Gardner WA Jr. Adenosquamous carcinoma of prostate. Urology. 1983;22(1):73–5.

  70. 70.

    Devaney DM, Dorman A, Leader M. Adenosquamous carcinoma of the prostate: a case report. Hum Pathol. 1991;22(10):1046–50.

  71. 71.

    Egilmez T, Bal N, Guvel S, Kilinc F, Ozkardes H. Adenosquamous carcinoma of the prostate. Int J Urol. 2005;12(3):319–21. https://doi.org/10.1111/j.1442-2042.2005.01036.x.

  72. 72.

    Humphrey PA. Histological variants of prostatic carcinoma and their significance. Histopathology. 2012;60(1):59–74. https://doi.org/10.1111/j.1365-2559.2011.04039.x.

  73. 73.

    Ishigooka M, Yaguchi H, Tomaru M, Sasagawa I, Nakada T, Mitobe K. Mixed prostatic carcinoma containing malignant squamous element. Reports of two cases. Scand J Urol Nephrol. 1994;28(4):425–7.

  74. 74.

    Mishra S, Goel H, Awasthi N, Puri A, Mahapatra R, Pal DK. Primary adenosquamous carcinoma of the prostate: a rare aggressive tumor. Clin Genitourin Cancer. 2014;12(1):e29–31. https://doi.org/10.1016/j.clgc.2013.08.006.

  75. 75.

    Moyana TN. Adenosquamous carcinoma of the prostate. Am J Surg Pathol. 1987;11(5):403–7.

  76. 76.

    Orhan D, Sak SD, Yaman O, Tulunay O, Gogus O. Adenosquamous carcinoma of the prostate. Br J Urol. 1996;78(4):646–7.

  77. 77.

    Regi P, Butturini G, Malleo G, Pedica F, D’Onofrio M, Bassi C. Clinicopathological features of adenosquamous pancreatic cancer. Langenbeck’s Arch Surg. 2011;396(2):217–22. https://doi.org/10.1007/s00423-010-0677-3.

  78. 78.

    Somerville TDD, Xu Y, Miyabayashi K, Tiriac H, Cleary CR, Maia-Silva D, et al. TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma. Cell Rep. 2018;25(7):1741–55. https://doi.org/10.1016/j.celrep.2018.10.051.

  79. 79.

    Harada T, Shimaoka K, Yakumaru K, Ito K. Squamous cell carcinoma of the thyroid gland—transition from adenocarcinoma. J Surg Oncol. 1982;19(1):36–43.

  80. 80.

    Rausch T, Benhattar J, Sutter M, Andrejevic-Blant S. Thyroid carcinoma with papillary and squamous features: report of a case with histogenetic considerations. Pathol Res Pract. 2010;206(4):263–9. https://doi.org/10.1016/j.prp.2009.05.003.

  81. 81.

    Gomi K, Kitagawa N, Usui Y, Tanaka M, Yoshida M, Hirata Y, et al. Papillary carcinoma with extensive squamous metaplasia arising from thyroglossal duct cyst in an 11-year-old girl: significance of differentiation from squamous cell carcinoma: a case report. J Pediatr Surg. 2011;46(4):e1–4. https://doi.org/10.1016/j.jpedsurg.2010.10.030.

  82. 82.

    Ahn S, Bae GE, Kim K-M. Exuberant squamous metaplasia of the gastric mucosa in a patient with gastric adenocarcinoma. Diagn Pathol. 2015;10:46. https://doi.org/10.1186/s13000-015-0281-5.

  83. 83.

    Zou M, Toivanen R, Mitrofanova A, Floch N, Hayati S, Sun Y, et al. Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. Cancer Discov. 2017;7(7):736–49. https://doi.org/10.1158/2159-8290.cd-16-1174.

  84. 84.

    Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22(3):298–305. https://doi.org/10.1038/nm.4045.

  85. 85.

    Alvarez MJ, Subramaniam PS, Tang LH, Grunn A, Aburi M, Rieckhof G, et al. A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. Nat Genet. 2018;50(7):979–89. https://doi.org/10.1038/s41588-018-0138-4.

  86. 86.

    Gong L, Yan Q, Zhang Y, Fang X, Liu B, Guan X. Cancer cell reprogramming: a promising therapy converting malignancy to benignity. Cancer Commun (London, England). 2019;39(1):48. https://doi.org/10.1186/s40880-019-0393-5.

  87. 87.

    Miura K, Mineta H, Yokota N, Tsutsui Y. Olfactory neuroblastoma with epithelial and endocrine differentiation transformed into ganglioneuroma after chemoradiotherapy. Pathol Int. 2001;51(12):942–7.

  88. 88.

    Glass T, Cochrane DD, Rassekh SR, Goddard K, Hukin J. Growing teratoma syndrome in intracranial non-germinomatous germ cell tumors (iNGGCTs): a risk for secondary malignant transformation-a report of two cases. Child’s Nerv Syst. 2014;30(5):953–7. https://doi.org/10.1007/s00381-013-2295-1.

  89. 89.

    Kesler KA, Patel JB, Kruter LE, Birdas TJ, Rieger KM, Okereke IC, et al. The “growing teratoma syndrome” in primary mediastinal nonseminomatous germ cell tumors: criteria based on current practice. J Thorac Cardiovasc Surg. 2012;144(2):438–43. https://doi.org/10.1016/j.jtcvs.2012.05.053.

  90. 90.

    Ghaouti M, Roquet L, Fazzalari L, Sibert L, Sabourin JC. “Growing teratoma syndrome”: an unrecognized complication of treated germ cell tumors of the testis. Ann Pathol. 2013;33(6):402–5. https://doi.org/10.1016/j.annpat.2013.10.020.

  91. 91.

    Okamoto I, Araki J, Suto R, Shimada M, Nakagawa K, Fukuoka M. EGFR mutation in gefitinib-responsive small-cell lung cancer. Ann Oncol. 2006;17(6):1028–9. https://doi.org/10.1093/annonc/mdj114.

  92. 92.

    Popat S, Wotherspoon A, Nutting CM, Gonzalez D, Nicholson AG, O’Brien M. Transformation to “high grade” neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma. Lung Cancer (Amsterdam, Netherlands). 2013;80(1):1–4. https://doi.org/10.1016/j.lungcan.2012.12.019.

  93. 93.

    Watanabe S, Sone T, Matsui T, Yamamura K, Tani M, Okazaki A, et al. Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma. Lung Cancer (Amsterdam, Netherlands). 2013;82(2):370–2. https://doi.org/10.1016/j.lungcan.2013.06.003.

  94. 94.

    Zhang Y, Li XY, Tang Y, Xu Y, Guo WH, Li YC, et al. Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR-tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma? Lung Cancer (Amsterdam, Netherlands). 2013;81(2):302–5. https://doi.org/10.1016/j.lungcan.2013.04.005.

  95. 95.

    Suda K, Murakami I, Sakai K, Mizuuchi H, Shimizu S, Sato K, et al. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer. Sci Rep. 2015;5:14447. https://doi.org/10.1038/srep14447.

  96. 96.

    Hui M, Uppin SG, Stalin BJ, Sadashivudu G. Histological transformation of adenocarcinoma to small cell carcinoma lung as a rare mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors: report of a case with review of literature. Lung India. 2018;35(2):160–3. https://doi.org/10.4103/lungindia.lungindia_347_17.

  97. 97.

    Santoni-Rugiu E, Grauslund M, Melchior LC, Costa JC, Sorensen JB, Urbanska EM. Heterogeneous resistance mechanisms in an EGFR exon 19-mutated non-small cell lung cancer patient treated with erlotinib: persistent FGFR3-mutation, localized transformation to EGFR-mutated SCLC, and acquired T790M EGFR-mutation. Lung Cancer (Amsterdam, Netherlands). 2017;113:14–7. https://doi.org/10.1016/j.lungcan.2017.08.024.

  98. 98.

    Tokaca N, Wotherspoon A, Nicholson AG, Fotiadis N, Thompson L, Popat S. Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer. Lung Cancer (Amsterdam, Netherlands). 2017;111:65–8. https://doi.org/10.1016/j.lungcan.2017.07.012.

  99. 99.

    Wahab A, Kesari K, Chaudhary S, Khan M, Khan H, Smith S, et al. Sequential occurrence of small cell and non-small lung cancer in a male patient: is it a transformation? Cancer Biol Ther. 2017;18(12):940–3. https://doi.org/10.1080/15384047.2017.1394546.

  100. 100.

    Xu Y, Huang Z, Gong L, Fan Y. A case of resistance to tyrosine kinase inhibitor therapy: small cell carcinoma transformation concomitant with plasma-genotyped T790M positivity. Anticancer Drugs. 2017;28(9):1056–61. https://doi.org/10.1097/cad.0000000000000540.

  101. 101.

    van Riel S, Thunnissen E, Heideman D, Smit EF, Biesma B. A patient with simultaneously appearing adenocarcinoma and small-cell lung carcinoma harbouring an identical EGFR exon 19 mutation. Ann Oncol. 2012;23(12):3188–9. https://doi.org/10.1093/annonc/mds525.

  102. 102.

    Kim WJ, Kim S, Choi H, Chang J, Shin HJ, Park CK, et al. Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor. Thorac Cancer. 2015;6(6):800–4. https://doi.org/10.1111/1759-7714.12217.

  103. 103.

    Alì G, Bruno R, Giordano M, Prediletto I, Marconi L, Zupo S, et al. Small cell lung cancer transformation and the T790M mutation: a case report of two acquired mechanisms of TKI resistance detected in a tumor rebiopsy and plasma sample of EGFR-mutant lung adenocarcinoma. Oncol Lett. 2016;12(5):4009–12. https://doi.org/10.3892/ol.2016.5193.

  104. 104.

    Alam N, Gustafson KS, Ladanyi M, Zakowski MF, Kapoor A, Truskinovsky AM, et al. Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung. Clin Lung Cancer. 2010;11(5):E1–4. https://doi.org/10.3816/CLC.2010.n.046.

  105. 105.

    Jiang SY, Zhao J, Wang MZ, Huo Z, Zhang J, Zhong W, et al. Small-cell lung cancer transformation in patients with pulmonary adenocarcinoma: a case report and review of literature. Medicine. 2016;95(6):e2752. https://doi.org/10.1097/md.0000000000002752.

  106. 106.

    Lin Q, Cai GP, Yang KY, Yang L, Chen CS, Li YP. Case report: small cell transformation and metastasis to the breast in a patient with lung adenocarcinoma following maintenance treatment with epidermal growth factor receptor tyrosine kinase inhibitors. BMC Cancer. 2016;16:593. https://doi.org/10.1186/s12885-016-2623-4.

  107. 107.

    Ma AT, Chan WK, Ma ES, Cheng T, Cheng PN. Small cell lung cancer with an epidermal growth factor receptor mutation in primary gefitinib-resistant adenocarcinoma of the lung. Acta Oncol (Stockholm, Sweden). 2012;51(4):557–9. https://doi.org/10.3109/0284186x.2011.636757.

  108. 108.

    Kudo K, Ohyanagi F, Horiike A, Miyauchi E, Yanagitani N, Hoshi R, et al. Clinicopathological findings of non-small-cell lung cancer with high serum progastrin-releasing peptide concentrations. Lung Cancer (Amsterdam, Netherlands). 2011;74(3):401–4. https://doi.org/10.1016/j.lungcan.2011.03.019.

  109. 109.

    Liu Y. Small cell lung cancer transformation from EGFR-mutated lung adenocarcinoma: a case report and literatures review. Cancer Biol Ther. 2018. https://doi.org/10.1080/15384047.2018.1435222.

  110. 110.

    Hwang KE, Jung JW, Oh SJ, Park MJ, Shon YJ, Choi KH, et al. Transformation to small cell lung cancer as an acquired resistance mechanism in EGFR-mutant lung adenocarcinoma: a case report of complete response to etoposide and cisplatin. Tumori. 2015;101(3):e96–8. https://doi.org/10.5301/tj.5000276.

  111. 111.

    Morinaga R, Okamoto I, Furuta K, Kawano Y, Sekijima M, Dote K, et al. Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer (Amsterdam, Netherlands). 2007;58(3):411–3. https://doi.org/10.1016/j.lungcan.2007.05.014.

  112. 112.

    Le T, Sailors J, Oliver DH, Mayer M, Hoskin S, Gerber DE. Histologic transformation of EGFR mutant lung adenocarcinoma without exposure to EGFR inhibition. Lung Cancer (Amsterdam, Netherlands). 2017;105:14–6. https://doi.org/10.1016/j.lungcan.2017.01.005.

  113. 113.

    Burkart J, Shilo K, Zhao W, Ozkan E, Ajam A, Otterson GA. Metastatic squamous cell carcinoma component from an adenosquamous carcinoma of the lung with identical epidermal growth factor receptor mutations. Case Rep Pulmonol. 2015;2015:4. https://doi.org/10.1155/2015/283875.

  114. 114.

    Haratani K, Hayashi H, Watanabe S, Kaneda H, Yoshida T, Takeda M, et al. Two cases of EGFR mutation-positive lung adenocarcinoma that transformed into squamous cell carcinoma: successful treatment of one case with rociletinib. Ann Oncol. 2016;27(1):200–2. https://doi.org/10.1093/annonc/mdv495.

  115. 115.

    Hsieh M-S, Jhuang J-Y, Hua S-F, Chou Y-H. Histologic evolution from adenocarcinoma to squamous cell carcinoma after gefitinib treatment. Ann Thorac Surg. 2015;99(1):316–9. https://doi.org/10.1016/j.athoracsur.2014.02.075.

  116. 116.

    Scher KS, Saldivar J-S, Fishbein M, Marchevsky A, Reckamp KL. EGFR-mutated lung cancer with T790M-acquired resistance in the brain and histologic transformation in the lung. J Natl Compr Cancer Netw. 2013;11(9):1040–4. https://doi.org/10.6004/jnccn.2013.0126.

  117. 117.

    Levin PA, Mayer M, Hoskin S, Sailors J, Oliver DH, Gerber DE. Histologic transformation from adenocarcinoma to squamous cell carcinoma as a mechanism of resistance to EGFR inhibition. J Thorac Oncol. 2015;10(9):e86–8. https://doi.org/10.1097/JTO.0000000000000571.

  118. 118.

    Clery E, Pisapia P, Feliciano S, Vigliar E, Marano A, De Luca C, et al. There is still a role for cytology in the ‘liquid biopsy’ era. A lesson from a TKI-treated patient showing adenocarcinoma to squamous cell carcinoma transition during disease progression. J Clin Pathol. 2017;70(9):798.

  119. 119.

    Park HK, Seo Y, Choi YL, Ahn MJ, Han J. Metastatic squamous cell carcinoma from lung adenocarcinoma after epidermal growth factor receptor tyrosine kinase inhibitor therapy. J Pathol Transl Med. 2017;51(4):441–3. https://doi.org/10.4132/jptm.2016.10.18.

  120. 120.

    Jukna A, Montanari G, Mengoli MC, Cavazza A, Covi M, Barbieri F, et al. Squamous cell carcinoma “transformation” concurrent with secondary T790M mutation in resistant EGFR-mutated adenocarcinomas. J Thorac Oncol. 2016;11(4):e49–51. https://doi.org/10.1016/j.jtho.2015.12.096.

  121. 121.

    Sato M, Matsui A, Shimoyama Y, Omote N, Morise M, Hase T, et al. An EGFR-mutated lung adenocarcinoma undergoing squamous cell carcinoma transformation exhibited a durable response to afatinib. Intern Med. 2018;57(23):3429–32. https://doi.org/10.2169/internalmedicine.0999-18.

  122. 122.

    Shinohara S, Ichiki Y, Fukuichi Y, Honda Y, Kanayama M, Taira A, et al. Squamous cell carcinoma transformation from adenocarcinoma as an acquired resistance after the EGFR TKI therapy in (EGFR-mutated) non-small cell lung cancer. J Thorac Dis. 2018;10(7):E526–31. https://doi.org/10.21037/jtd.2018.06.83.

  123. 123.

    Kuiper JL, Ronden MI, Becker A, Heideman DAM, van Hengel P, Ylstra B, et al. Transformation to a squamous cell carcinoma phenotype of an EGFR-mutated NSCLC patient after treatment with an EGFR-tyrosine kinase inhibitor. J Clin Pathol. 2015;68(4):320–1.

  124. 124.

    Izumi H, Yamasaki A, Ueda Y, Sumikawa T, Maeta H, Nakamoto S, et al. Squamous cell carcinoma transformation from EGFR-mutated lung adenocarcinoma: a case report and literature review. Clin Lung Cancer. 2018;19(1):e63–6. https://doi.org/10.1016/j.cllc.2017.10.005.

  125. 125.

    Longo L, Mengoli MC, Bertolini F, Bettelli S, Manfredini S, Rossi G. Synchronous occurrence of squamous-cell carcinoma “transformation” and EGFR exon 20 S768I mutation as a novel mechanism of resistance in EGFR-mutated lung adenocarcinoma. Lung Cancer (Amsterdam, Netherlands). 2017;103:24–6. https://doi.org/10.1016/j.lungcan.2016.11.012.

  126. 126.

    Jay G, Jeffrey PG, Weijie M, Ken Y, Elizabeth HM, Megan ED, et al. Squamous cell transformation of primary lung adenocarcinoma in a patient with EML4-ALK fusion variant 5 refractory to ALK inhibitors. J Natl Compr Cancer Netw. 2019;17(4):297–301. https://doi.org/10.6004/jnccn.2019.7291.

  127. 127.

    Park S, Han J, Sun J-M. Histologic transformation of ALK-rearranged adenocarcinoma to squamous cell carcinoma after treatment with ALK inhibitor. Lung Cancer (Amsterdam, Netherlands). 2019;127:66–8. https://doi.org/10.1016/j.lungcan.2018.11.027.

  128. 128.

    Bugano DDG, Kalhor N, Zhang J, Neskey M, William WN. Squamous-cell transformation in a patient with lung adenocarcinoma receiving erlotinib: co-occurrence with T790M mutation. Cancer Treat Commun. 2015;4(Supplement C):34–6. https://doi.org/10.1016/j.ctrc.2015.03.007.

  129. 129.

    Hsu C-L, Chen K-Y, Kuo S-W, Chang Y-L. Histologic transformation in a patient with lung cancer treated with chemotherapy and pembrolizumab. J Thorac Oncol. 2017;12(6):e75–6. https://doi.org/10.1016/j.jtho.2017.02.006.

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YC and HJ conceived the idea and wrote the manuscript. WYT revised the background and clinical case report section. XT help revised the part about lung adenocarcinoma to squamous cell carcinoma transdifferentiation. All authors read and approved the final manuscript.

Correspondence to Hongbin Ji.

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Chen, Y., Tang, W.Y., Tong, X. et al. Pathological transition as the arising mechanism for drug resistance in lung cancer. Cancer Commun 39, 53 (2019) doi:10.1186/s40880-019-0402-8

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Keywords

  • Lung cancer
  • Drug resistance
  • Pathological transition