Anaplastic lymphoma kinase (ALK) is a potent oncogenic driver in lung cancer. ALK tyrosine kinase inhibitors yield significant benefit in patients with ALK fusion-positive (ALK+) lung cancers; yet the durability of response is limited by drug resistance. Elucidation of on-target resistance mechanisms has facilitated the development of next-generation ALK inhibitors, but overcoming ALK-independent resistance mechanisms remains a challenge. In this Review, we discuss the molecular underpinnings of acquired resistance to ALK-directed therapy and highlight new treatment approaches aimed at inducing long-term remission in ALK+ disease.
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