Table 1.
Bypass pathways identified as mediators of crizotinib resistance
| Pathway/signal | Mechanism of activation | Potential combinations/agentsa | Reference |
|---|---|---|---|
| EGFR | Ligand secretion (EGF, amphiregulin, neuregulin 1) | Crizotinib + dacomitinib Crizotinib + gefitinib Crizotinib + erlotinib |
[28, 29, 32, 33] |
| cKIT | Amplification, ligand secretion (stem cell factor) | Crizotinib + imatinib | [29] |
| IGF-IR | Ligand secretion (IGF-1) | Crizotinib + linsitinib Ceritinibb |
[34] |
| HER2/HER3 | Ligand secretion (EGF, neuregulin 1) | Crizotinib + lapatinib | [32, 35] |
| SRC | The mechanism is unknown. ALK inhibition is speculated to lead to SRC upregulation via release of a negative regulatory signal | Crizotinib + saracatinib Crizotinib + dasatinib |
[36] |
| P2Y purinergic receptors | Activation of protein kinase C | Crizotinib + sotrastaurin | [35] |
| MAPK | Wild-type KRAS copy number gain, downregulation of DUSP6 | Crizotinib + trametinib | [37] |
aSimilar combinations are active in preclinical models and have not been validated in clinical trials.
bNote: toxicity limits dosing ceritinib in patients at a level necessary to inhibit IGF-1R.