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Ref Type Journal Article
PMID (30089600)
Authors Ai X, Niu X, Chang L, Chen R, Ou SI, Lu S
Title Next generation sequencing reveals a novel ALK G1128A mutation resistant to crizotinib in an ALK-Rearranged NSCLC patient.
Journal Vol Issue Date Pages Journal Short Title
Lung cancer (Amsterdam, Netherlands) 123 2018 Sep 83-86 Lung Cancer
URL
Abstract Text Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged non-small cell lung cancer (NSCLC) patients who are resistant to treatment with the ALK inhibitor crizotinib. We sought to uncover novel mutations that contribute to resistance in these patients.Following clinical diagnosis and development of crizotinib treatment resistance, tissue and ctDNA samples were obtained from the 60-year-old patient and subjected to next-generation sequencing for identification of mutations contributing to drug resistance.We identified a novel acquired NSCLC ALK G1128A mutation in the ALK + NSCLC patient who progressed on crizotinib after a short partial response to the drug. This mutation, ALK G1128A, is located at the glycine loop (the P-loop) of the ALK tyrosine kinase domain. As a gain-of-function mutation, ALK G1128A increases kinase activity and transformation ability, perhaps conferring resistance to crizotinib.This case further illustrates the importance of comprehensive genomic profiling of resistant tumors for tailoring treatment decisions after disease progression on crizotinib in ALK + NSCLC in the era of rapidly developing new-generation ALK inhibitors and other therapeutic strategies.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK G1128A ALK R1192P lung adenocarcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, ALK G1128A and ALK R1192P were identified in the post-progression biopsy of a patient with lung adenocarcinoma harboring EML4-ALK who previously responded to treatment with Xalkori (crizotinib) (PMID: 30089600). 30089600