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  • Review Article
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ALK-positive lung cancer: a moving target

Abstract

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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Fig. 1: Oncogenic ALK signaling.
Fig. 2: Resistance in ALK+ lung cancer and therapeutic interventions.
Fig. 3: Forward-looking treatment paradigms in advanced ALK+ lung cancer.

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Acknowledgements

We thank patients and their families for their heroic efforts in contributing to and advocating for ALK+ lung cancer research. We apologize to the numerous colleagues whose important contributions may not have been cited in this Review due to space constraints. J.L.S. is supported by A Breath of Hope Lung Foundation and the Lung Cancer Research Foundation. J.J.L. is supported in part by NIH/NCI R01CA164273.

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Correspondence to Alice T. Shaw.

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J.L.S. has received honoraria from the Academy of Continued Healthcare Learning, Springer Healthcare and Targeted Oncology. J.J.L. has served as a compensated consultant for Genentech, Regeneron, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics and Turning Point Therapeutics; received honorarium and travel support from Pfizer; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent and Novartis; and received CME funding from OncLive, MedStar Health and Northwell Health. A.T.S. is currently employed by Novartis.

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Schneider, J.L., Lin, J.J. & Shaw, A.T. ALK-positive lung cancer: a moving target. Nat Cancer 4, 330–343 (2023). https://doi.org/10.1038/s43018-023-00515-0

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