Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

Cancers
Geeta Geeta SharmaRoberto Chiarle

Abstract

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along ...Continue Reading

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Citations

Jan 19, 2019·Expert Review of Clinical Pharmacology·Junyi Yang, Weiliang Gong
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Aug 28, 2021·Biomedicines·Irina Palacín-AlianaÁngel Ayuso-Sacido

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Methods Mentioned

BETA
xenograft
biopsy

Clinical Trials Mentioned

NCT01871805
NCT01801111
NCT02094573
NCT02737501
NCT03052608
NCT02521051
NCT02292550
NCT02321501
NCT01998126
NCT02511184

Software Mentioned

ssGSEA )

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