Table 2.

Main categories and examples of different acquired drug resistance mechanisms

Acquired resistance mechanismExample
Secondary genetic alteration in drug target 
Mutation in drug contact residueABL T315I
Mutation in noncontact residue leading to altered conformationABL G250E
Mutation leading to increased ATP affinityEGFR T790M; ALK F1174L
AmplificationBCR-ABL
Alternative spliced formp61BRAF V600E
Bypass mechanism 
Activation of parallel signaling pathwayMET amplification (erlotinib resistance)
 COT or RTK overexpression (vemurafenib resistance)
Alterations in upstream or downstream effectors 
Upstream effectorBRAF amplification; selumetinib resistance
Downstream effectorMEK1/2 mutation; vemurafenib resistance
 NRAS mutation, vemurafenib resistance
Pathway independent 
Epithelial–mesenchymal transitionEGFR inhibitor resistance
Changes in tumor microenvironmentJAK2 inhibitor resistance
Altered angiogenesisEGFR inhibitor resistance