Reference Detail

Ref Type

Journal Article

PMID

(25594040)

Authors

Carlino MS, Todd JR, Rizos H

Title

Resistance to c-Kit inhibitors in melanoma: insights for future therapies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncoscience	1	6	2014	423-6	Oncoscience

URL

Abstract Text

Mutations activating the receptor tyrosine kinase c-Kit occur commonly in melanomas arising on mucosal membranes and acral skin. Clinical studies have demonstrated that selective inhibition of c-Kit is effective in treating patients with c-Kit mutant gastrointestinal stromal tumors, but c-Kit inhibitor activity has been disappointing in c-Kit mutant melanoma patients. Activated c-Kit utilises phosphatidylinositol 3-kinase (PI3K) signalling as the dominant effector of cell proliferation and survival with the mitogen-activated protein kinase (MAPK) cascade serving as an ancillary survival pathway. We confirmed that these pathways are re-activated in melanoma cells with acquired resistance to c-Kit inhibitors and that these resistant sublines remain sensitive to the concurrent inhibition of MAPK and PI3K signalling. These findings suggest that durable responses in c-Kit mutant melanoma may require combination therapies that selectively inhibit critical downstream proliferative and survival pathways. We also discuss the interaction between targeted therapies and anti-tumor immune responses and the need to consider immunotherapies in new combinatorial treatment approaches.

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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
KIT T670I	melanoma	resistant	Nilotinib	Preclinical	Actionable	In a preclinical study, melanoma cells expressing KIT T670I demonstrated resistance to treatment with Tasigna (nilotinib) (PMID: 23582185, PMID: 25594040).	23582185 25594040
KIT T670I	melanoma	resistant	Dasatinib	Preclinical	Actionable	In a preclinical study, melanoma cells expressing KIT T670I demonstrated resistance to treatment with Sprycel (dasatinib) (PMID: 23582185, PMID: 25594040).	23582185 25594040
KIT A829P	melanoma	sensitive	Nilotinib	Preclinical	Actionable	In a preclinical study, Tasigna (nilotinib) demonstrated efficacy by inhibiting proliferation of cultured melanoma cells expressing KIT A829P (PMID: 23582185, PMID: 25594040).	23582185 25594040
KIT A829P	melanoma	resistant	Imatinib	Preclinical	Actionable	In a preclinical study, melanoma cells expressing KIT A829P demonstrated resistance to treatment with Gleevec (imatinib mesylate) (PMID: 23582185, PMID: 25594040).	23582185 25594040
KIT A829P	melanoma	sensitive	Dasatinib	Preclinical	Actionable	In a preclinical study, Sprycel (dasatinib) demonstrated efficacy by inhibiting proliferation of cultured melanoma cells expressing KIT A829P (PMID: 23582185, PMID: 25594040).	23582185 25594040
KIT T670I	melanoma	sensitive	Sunitinib	Preclinical	Actionable	In a preclinical study, Sutent (sunitinib) demonstrated efficacy by inhibiting proliferation of cultured melanoma cells expressing KIT T670I (PMID: 23582185, PMID: 25594040).	23582185 25594040
KIT A829P	melanoma	resistant	Sunitinib	Preclinical	Actionable	In a preclinical study, melanoma cells expressing KIT A829P demonstrated resistance to treatment with Sutent (sunitinib) (PMID: 23582185, PMID: 25594040).	23582185 25594040
KIT T670I	melanoma	resistant	Imatinib	Preclinical	Actionable	In a preclinical study, melanoma cells expressing KIT T670I demonstrated resistance to treatment with Gleevec (imatinib mesylate) (PMID: 23582185, PMID: 25594040).	23582185 25594040