Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	19	5	2011 May 17	679-90	Cancer Cell

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	221	31

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Alectinib	Alecensa	CH5424802\|RO5424802	ALK Inhibitor 32 RET Inhibitor 52	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 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 - Biochemical	Actionable	In a preclinical study, ALK C1156Y was sensitive to Alecensa (alectinib) in an in vitro enzyme assay (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 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