Reference Detail

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
No data available in table

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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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).

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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	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
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 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	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	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 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 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 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

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