Resistance to ALK TKI therapy can be either primary or acquired1

Primary resistance implies an intrinsic lack of response to treatment.1 Acquired resistance implies disease progression after initial response (partial or complete) to treatment.1

Although primary resistance is poorly understood, acquired resistance can fall broadly under two categories:1

ALK-dependent resistance mechanisms
Secondary mutations in the ALK tyrosine kinase domain

ALK-independent resistance mechanisms
Activation of bypass signaling pathways

Acquired resistance can emerge from a wide spectrum of ALK-dependent or ALK-independent mechanisms of resistance following first-line ALK TKI therapy.1–4

ALK-dependent resistance mechanisms, such as point mutations in the ALK tyrosine kinase domain and ALK gene amplification, are known to alter ALK TKI therapy sensitivity.1,2

ALK-independent resistance mechanisms involve the activation of bypass signaling pathways through genetic alteration and lead to tumor cell survival and proliferation even after ALK inhibition.1

The point mutation patterns observed in patients with ALK+ NSCLC following ALK TKI therapy are highly heterogeneous.2,5

Most patients who respond to first-generation ALK TKI therapy will eventually relapse due to acquired resistance2,4

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ALK(+): anaplastic lymphoma kinase (positive); NSCLC: non-small-cell lung cancer; TKI: tyrosine kinase inhibitor.