Table 2.
Exemplary Mechanisms of Acquired Resistance to Kinase Inhibitors
| Targeted Agent | Target Gene | Acquired Resistance via Secondary Mutation, Amplification, or Activation of Target | Acquired Resistance via Bypass | Acquired Resistance via Downstream Mutation |
|---|---|---|---|---|
| Imatinib | ||||
| ABL | T315I | IGF1R amplification | ||
| Y253F/H | AXL overexpression*† | |||
| E255K/V | ||||
| ABL amplification | ||||
| T670I | ||||
| V654A | ||||
| D816A/G/H/V | ||||
| D820A/E/G/Y | ||||
| KIT | Y823D | |||
| KIT amplification | ||||
| PDGFRA | T674I | |||
| Gefitinib or erlotinib | EGFR | T790M | MET amplification | |
| D761Y | HGF overexpression*† | |||
| L747S | IGFBP3 loss*† | |||
| T854A | ||||
| EGFR amplification* | ||||
| Trastuzumab | HER2 | |||
| Lapatinib | HER2/EGFR | |||
| PKC412 | FLT3 | N676K | ||
| FGFR | ||||
| AZD6044 | MEK1 | MEK1 P124L | ||
| BRAF amplification* | ||||
| PLX4032 | BRAF | NRAS Q61K | COT overexpression† | MEK1 C121S |
| PDGFRβ overexpression† | ||||
| CRAF overexpression*† | ||||
| AXL overexpression*† | ||||
| HER2 overexpression*† | ||||
| Crizotinib | ALK/MET | L1196M | ||
| C1156Y | ||||
| F1174L |
Abbreviations: IGF1R, insulin-like growth factor 1 receptor; HGF, hepatocyte growth factor; IGFBP3, insulin-like growth factor receptor binding protein-3; PDGFRβ, platelet-derived growth factor β; HER2, human epidermal growth factor receptor 2.
*
Mechanisms that have been described in vitro.
†
Nongenetic mechanisms.