Table 1. Examples of approved oncogene‐targeted therapies and observed resistance mechanisms in patients
Target/indicationInhibitor(s)Observed clinical responsesResistance mechanisms
Secondary oncogene mutationPathway mutationsBypass
BCR‐ABL mutant CMLImatinib, nilotinib, dasatinib, ponatinibComplete cytogenetic responses: 65–80% [9], [112], [113], [166]T315I and other mutations, BCR‐ABL amplification [26], [167], [168]SRC family upregulation FGF2/FGFR3 activation [168], [169]
KIT mutant GISTImatinib53.7% partial response in patients with refractory disease [170]KIT mutations (e.g., V654A, T670I) or amplification [171], [172] PDGFRA mutation [172]
Rhabdomyosarcomatous differentiation [109]
BRAF mutant melanomaVemurafenib, dabrafenib 45–51% response rate;
benefits observed versus prior standard of care [58], [59], [173]
P61‐BRAF splice variant [28];
BRAF amplification [174]
NRAS, NF1, MAP2K1, MAP2K2 mutation
MITF amplification [31], [32], [33], [175], [176]
PI3K pathway mutations; CRAF, RTK, COT, AXL upregulation [29], [31], [33], [110], [175], [176], [177]
EGFR mutant NSCLCGefitinib, erlotinib, afatinib 9–13 months progression‐free survival; 73.7% response rate for gefitinib;
benefit versus standard chemotherapy [178], [179], [180], [181], [182]
T970M mutation (+/− gene amplification ~40–65%);
other EGFR point mutations (~1–2%) [105], [183], [184], [185]
PIK3CA mutation, BRAF mutation (~1%) [105], [185]MET or HER2 amplification, histologic transformation (EMT, SCLC ~12–14%) [37], [38], [105], [185], [186]
EGFR‐amplified colorectal cancerCetuximab, panitumumabImprovements in progression‐free survival versus best supportive care [187]KRAS, BRAF, PIK3CA, PTEN mutation [187]
ALK‐translocated NSCLCCrizotinib, ceritinib, alectinib55–65% response rate; improved response rate versus standard chemotherapy [116], [117], [188]L1196M, I1171T, V1180L, and other mutations, with or without amplification (~28–65%) [185], [189], [190], [191]KRAS mutation [191]KIT amplification, EGFR upregulation or mutation, IGF‐1R upregulation [190], [191], [192]
HER2/ERBB2‐amplified breast cancerTrastuzumab, lapatinib, pertuzumabTrastuzumab: 33% combined complete and partial response rate [193]; Lapatinib: 39% partial response rate [194]Trastuzumab epitope mutations: p95‐HER2, D16 [27], [195]PIK3CA/PTEN mutation [196]EGFR, HER3, HER4, IGF‐1R, MET upregulation and heterodimerization [195], [196]
ROS1‐translocated NSCLCCrizotinib72% objective response rate [197]G2032R mutation [198]
RET mutant medullary thyroid carcinoma (MTC)Vandetanib46% objective response rate in patients with hereditary MTC harboring RET mutation [199]
Retinoic acid receptor (RARA)‐translocated APLATRA Complete response rates of > 90%;
superior to prior chemotherapy regimens [200]
Ligand‐binding domain mutation (~40%) [11], [201]
AR‐positive castration‐resistant prostate cancerEnzalutamide18.4‐month overall survival, 54% PSA reduction [202]F876L mutation [99], [100], [101], AR‐V7 ligand‐binding domain truncation [203]GR upregulation [203]
ER‐positive metastatic breast cancerTamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestaneTamoxifen: approximately 50% drop in mortality with 10 years of treatment [204]Ligand‐binding domain mutation [30], [205]