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Ref Type Journal Article
PMID (21575866)
Authors Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y
Title CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
Journal Cancer cell
Vol 19
Issue 5
Date 2011 May 17
URL
Abstract Text Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.

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Molecular Profile Treatment Approach
EML4 - ALK ALK C1156Y Alectinib
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Alectinib Alectinib 113 12
Drug Name Trade Name Synonyms Drug Classes Drug Description
Alectinib Alecensa CH5424802|RO5424802 ALK Inhibitor 22 RET Inhibitor 39 Alecensa (alectinib) is an inhibitor of RET and ALK, including ALK fusions and the gatekeeper mutation, L1196M (PMID: 21575866, PMID: 25349307). Alecensa (alectinib) is FDA-approved for use in patients with ALK-positive (rearrangements and fusions) non-small cell lung cancer (FDA.gov).
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 L1196M Advanced Solid Tumor conflicting Alectinib Preclinical - Cell line xenograft Actionable In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells expressing an EML4-ALK fusion and ALK L1196M in culture and in cell line xenograft models (PMID: 21575866). 21575866
EML4 - ALK lung non-small cell carcinoma sensitive Alectinib Preclinical - Cell line xenograft Actionable In a preclinical study, Alecensa (alectinib) inhibited Alk phosphorylation and growth of a human non-small cell lung cancer cell line harboring EML4-ALK in culture and in cell line xenograft models (PMID: 21575866). 21575866
EML4 - ALK ALK C1156Y Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing EML4-ALK with ALK C1156Y were sensitive to Alecensa (alectinib) in culture (PMID: 21575866). 21575866
ALK C1156Y Advanced Solid Tumor sensitive Alectinib Preclinical Actionable In a preclinical study, ALK C1156Y was sensitive to Alecensa (alectinib) in an in vitro enzyme assay (PMID: 21575866). 21575866