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Ref Type Journal Article
PMID (29054983)
Authors Couts KL, Bemis J, Turner JA, Bagby SM, Murphy D, Christiansen J, Hintzsche JD, Le A, Pitts TM, Wells K, Applegate A, Amato C, Multani P, Chow-Maneval E, Tentler JJ, Shellman YG, Rioth MJ, Tan AC, Gonzalez R, Medina T, Doebele RC, Robinson WA
Title ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms.
Journal Molecular cancer therapeutics
Vol 17
Issue 1
Date 2018 01
URL
Abstract Text Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI ) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 of 45 (24.4%) melanomas. Ten melanomas express wild-type (wt) ALK and/or ALKATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo, the melanomas expressing wt ALK or ALKATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALKATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy, whereas melanomas expressing ALKATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALKATIMol Cancer Ther; 17(1); 222-31. ©2017 AACR.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK mucosal melanoma sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, Rozlytrek (entrectinib) decreased viability of a mucosal melanoma cell line harboring EML4-ALK in culture (PMID: 29054983). 29054983
EML4 - ALK mucosal melanoma sensitive Crizotinib Preclinical - Cell line xenograft Actionable In a preclinical study, Xalkori (crizotinib) inhibited downstream signaling and decreased viability of a mucosal melanoma cell line expressing EML4-ALK in culture and inhibited tumor growth in a cell line xenograft model (PMID: 29054983). 29054983
EML4 - ALK mucosal melanoma sensitive ASP3026 Preclinical - Cell culture Actionable In a preclinical study, ASP3026 decreased viability of a mucosal melanoma cell line harboring EML4-ALK in culture (PMID: 29054983). 29054983
NRAS Q61H mucosal melanoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited downstream signaling and decreased viability of a mucosal melanoma cell line harboring NRAS Q61H in culture (PMID: 29054983). 29054983
EML4 - ALK mucosal melanoma sensitive Ceritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Zykadia (ceritinib) decreased viability of a mucosal melanoma cell line harboring EML4-ALK in culture and inhibited tumor growth in a cell line xenograft model (PMID: 29054983). 29054983
EML4 - ALK mucosal melanoma sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) decreased viability of a mucosal melanoma cell line harboring EML4-ALK in culture (PMID: 29054983). 29054983