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Table 1 Pharmacogenomics of cetuximab and erlotinib: potential biomarkers that are predicative of drug efficacy

From: Pharmacogenomics of EGFR-targeted therapies in non–small cell lung cancer: EGFR and beyond

Biomarker Cetuximab Erlotinib
EGFR biomarkers
EGFR Expression profile that incurs sensitivity: Mutations that incur sensitivity [1]:
♦High EGFR expression (as determined by IHC in NSCLC [11,13,60,61] and flow cytometry in colorectal cancer [12]) ♦Exon 19 deletions
♦L858R
♦G719X (X = C, S, or A)
♦L861Q
Expression profile that incurs resistance: Mutations that incur resistance (primarily exon 20 insertions) [1]:
♦Low EGFR expression (as determined by IHC) [6,11,13,60,61] ♦T790M
♦L747S
♦D761Y
♦T854A
Biomarkers in downstream components of the EGFR signaling
KRAS Little predictive value in NSCLC [16,68] Mutations that incur resistance (exon 1 point mutations) [1,17,66] :
♦G12X
♦G13X
PIK3CA Mutations that incur resistance (in colorectal cancer and human head and neck cancer) Activating mutations that incur resistance [72,73,76]
Exon 20 kinase domain mutations: Exon 9 helical domain mutations:
♦H1047X (primarily H1047R) [77-79] ♦E542X (primarily E542K)
♦E545X (primarily E545K)
Exon 20 kinase domain mutation:
♦H1047X (primarily H1047R)
PTEN Mutations that incur resistance: Mutations that incur resistance [80]:
♦Homozygous PTEN deletions ♦Homozygous PTEN deletions
♦Missense/loss of function mutations [114] ♦Missense/loss of function mutations
Expression profile that incurs resistance: Expression profile that incurs resistance:
♦Low/null PTEN expression [81,82]
♦Null PTEN expression [83,84] Expression profile that incurs sensitivity:
♦High PTEN expression [81]
NF-κB Expression profile that incurs sensitivity: Factors that enhance sensitivity:
♦Low NF-κB (as determined by evidence from patients with colorectal cancer [88]) ♦Low NF-κB expression (via knockdown of RELA subunit) [87]
Expression profile that incurs resistance: ♦Inactive NF-κB associated with increased inhibitor of NF-κB (NFKBIA) expression [87]
♦High NF-κB (as determined by evidence from patients with colorectal cancer [88]) Factors that enhance resistance:
  ♦High NF-κB (as determined by NF-κB overexpression)
♦Overactive NF-κB (via NFKBIA knockdown [87], IKK overexpression [87], and high levels of AEG-1 [1])
Biomarkers in other RTKs
MET Incurred resistance from: Incurred resistance from:
MET amplification [98] MET gene amplification [92,93,96]
♦MET activation [98,99] ♦Enhanced MET signaling dependent on HER3 [97]
♦Increased concentrations of HGF ligand [94]
HER2 Incurred resistance from: Incurred resistance from:
♦Enhanced copy number of HER2 gene [103] ♦Enhanced copy number of HER2 gene [103]
♦HER2-mediated signaling [101,103] ♦Activating HER2 mutations in exons 18–21 (kinase domain), notably 12-bp duplication/insertion of YVMA in exon 20 at codon 776 (HERYVMA) [103]
HER3 Incurred resistance from: Incurred sensitivity from:
♦Enhanced EGFR/HER3 activity via up-regulated HER3 [101] ♦Low HER3 expression [115]
♦Dimerization and transactivation of HER2/3 in an EGFR-dependent manner [101] ♦Down-regulation of HER3 by RNAi in EGFR-mutant and wild-type EGFR cell lines [97]
Restored sensitivity from:
♦Down-regulation of HER3 by siRNA [101]
  1. EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma oncogene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PTEN, phosphatase and tensin homolog; NF-κB, nuclear factor kappa-B; RTK, receptor tyrosine kinase; MET, hepatocyte growth factor receptor; HER2/3, human epidermal growth factor receptor 2/3; siRNA, small interfering RNA; IHC, immunohistochemistry; NSCLC, non–small cell lung cancer; RELA, rel homology domain A; NFKBIA, nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha; IKK, IκB kinase; AEG-1, astrocyte elevated gene-1; HGF, hepatocyte growth factor; RNAi, RNA interference.