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Ref Type Journal Article
PMID (26032424)
Authors Maxson JE, Davare MA, Luty SB, Eide CA, Chang BH, Loriaux MM, Tognon CE, Bottomly D, Wilmot B, McWeeney SK, Druker BJ, Tyner JW
Title Therapeutically Targetable ALK Mutations in Leukemia.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 75 11 2015 Jun 01 2146-50 Cancer Res
URL
Abstract Text Genome sequencing is revealing a vast mutational landscape in leukemia, offering new opportunities for treatment with targeted therapy. Here, we identify two patients with acute myelogenous leukemia and B-cell acute lymphoblastic leukemia whose tumors harbor point mutations in the ALK kinase. The mutations reside in the extracellular domain of ALK and are potently transforming in cytokine-independent cellular assays and primary mouse bone marrow colony formation studies. Strikingly, both mutations conferred sensitivity to ALK kinase inhibitors, including the FDA-approved drug crizotinib. On the basis of our results, we propose that tumors harboring ALK mutations may be therapeutically tractable for personalized treatment of certain aggressive leukemias with ALK inhibitors.

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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
ALK A348D missense gain of function ALK A348D lies within MAM domain 1 of the Alk protein (UniProt.org). A384D confers a gain of function to the Alk protein as demonstrated by increased cell proliferation in the absence of growth factor and colony formation in culture (PMID: 26032424).
ALK F856S missense gain of function ALK F856S lies within the extracellular domain of the Alk protein (UniProt.org). F856S confers a gain of function to the Alk protein as demonstrated by increased cell proliferation in the absence of growth factor (PMID: 26032424, PMID: 34646012) and colony formation in culture (PMID: 26032424).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK F856S hematologic cancer sensitive GSK1838705A Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK F856S were sensitive to treatment with GSK1838705A in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424
ALK A348D hematologic cancer sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK A348D were sensitive to treatment with Xalkori (crizotinib) in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424
ALK A348D hematologic cancer sensitive TAE684 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK A348D were sensitive to treatment with TAE684 in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424
ALK F856S hematologic cancer sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK F856S were sensitive to treatment with Zykadia (ceritinib) in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424
ALK F856S hematologic cancer sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK F856S were sensitive to treatment with Alunbrig (brigatinib) in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424
ALK A348D hematologic cancer sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK A348D were sensitive to treatment with Alunbrig (brigatinib) in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424
ALK F856S hematologic cancer sensitive TAE684 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK F856S were sensitive to treatment with TAE684 in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424
ALK A348D hematologic cancer sensitive GSK1838705A Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK A348D were sensitive to treatment with GSK1838705A in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424
ALK F856S hematologic cancer sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK F856S were sensitive to treatment with Xalkori (crizotinib) in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424
ALK A348D hematologic cancer sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK A348D were sensitive to treatment with Zykadia (ceritinib) in culture, demonstrating decreased cell viability (PMID: 26032424). 26032424