Targeted therapy: resistance and re-sensitization

Cancer Communications

Table 1 Anti-cancer drugs for targeted therapy

Target	First-line drug(s)	Principal indication(s)	Potential resistance mechanism(s)	Re-sensitization agent(s)	References
BCR-ABL fusion	Imatinib	CML	Fixing the kinase domain in its active configuration	1. Dasatinib 2. Nilotinib 3. Ponatinib	[7, 8]
KIT	Imatinib	GIST Melanoma Sarcoma	1. Mutations of c-KIT axons 9/11 2. PDGFRA (D842 V) mutation	1. Sunitinib 2. Regorafenib	[7, 8]
EGFR	Gefitinib Erlotinib Cetuximab	NSCLC Colorectal cancer	1. Secondary mutations in EGFR such as T790 M “gatekeeper” mutation 2. Multi-signaling cascade-driven disorders 3. EGFR S492R mutation	1. Cetuximab + Afatinid 2. Rociletinib 3. Panitumumab	[9–13]
ALK rearrangement	Crizotinib	NSCLC	Secondary mutations in ALK rearrangement	Ceritinib Alertinib	[14, 15]
HER2	Trastuzumab	Breast cancer Gastric cancer	1. Lack of the extracellular domain of HER2 2. Enhanced Her2 dimerization	1. Pertuzumab 2. Herceptin emtansine 3. Lapatinib	[16, 17]
VEGF/VEGFR	Bevacizumab Ramucirumab Sorafenib Sunitinib Aflibercept Pazopanib Vandetanib Vatalanib Cediranib Axitinib	Renal cancer Colorectal cancer Small cell lung cancer Thyroid cancer Sarcoma	1. Alternative angiogenic signaling 2. Increased HIF1, MDSCs, CSCs, etc.	1. Alternative angiogenic inhibitors 2. CSC inhibitors	[18–21]
BRAF	Vemurafenib Dabrafenib	Melanoma	1. BRAF amplification and new BRAF V600E splice isoforms 2. BRAF-independent MAPK activation	1. Vemurafenib + Cobimetinib 2. Dabrafenib + Trametinib 3. Anti-PD-1/PD-L1 antibodies	[22–24]

BCR-ABL breakpoint cluster region-Abelson, CML chronic myeloid leukemia, KIT kit receptor tyrosine kinase, GIST gastrointestinal stromal tumor, PDGFRA platelet-derived growth factor receptor A, EGFR epidermal growth factor receptor, NSCLC non–small cell lung cancer, ALK anaplastic lymphoma kinase, HER2 human EGFR2, VEGF(R) vascular endothelial cell growth factor (receptor), HIF1 hypoxia-inducible factor 1, MDSC myeloid-derived suppressor cell, CSC cancer stem cell, BRAF raf murine sarcoma viral oncogene homolog B, MAPK mitogen-activated protein kinase, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1

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