Reference Detail

Ref Type

Journal Article

PMID

(20979473)

Authors

Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H, Ishikawa Y, Kimura H, Mitsudomi T, Tanio Y, Mano H

Title

EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The New England journal of medicine	363	18	2010 Oct 28	1734-9	N Engl J Med

URL

Abstract Text

The EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers, and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way. Here, we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to two different ALK inhibitors. (Funded by the Ministry of Health, Labor, and Welfare of Japan, and others.).

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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	C1156Y	missense	unknown	ALK C1156Y lies within the protein kinase domain of the Alk protein (UniProt.org). C1156Y has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK fusions (PMID: 21613408, PMID: 20979473, PMID: 27490033, PMID: 27045755), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Nov 2023).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK C1156Y ALK L1196M	lung adenocarcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with lung adenocarcinoma harboring EML4-ALK treated on a clinical trial achieved a partial response when treated with Xalkori (crizotinib), however, after 5 months, the patient progressed and was found to harbor secondary resistance mutations, ALK C1156Y and ALK L1196M (PMID: 20979473; NCT00585195).	20979473