Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	17	1	2018 01	222-231	Mol Cancer Ther

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	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
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	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
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	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