Reference Detail

Ref Type

Journal Article

PMID

(23582185)

Authors

Todd JR, Becker TM, Kefford RF, Rizos H

Title

Secondary c-Kit mutations confer acquired resistance to RTK inhibitors in c-Kit mutant melanoma cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Pigment cell & melanoma research	26	4	2013 Jul	518-26	Pigment Cell Melanoma Res

URL

Abstract Text

Activation of the c-Kit receptor tyrosine kinase is rare in melanoma, but occurs in 20-40% of melanoma arising on mucosal membranes, acral skin and skin with chronic sun-induced damage. Many activating c-Kit mutations have been shown to be highly sensitive to imatinib mesylate, although the majority of patients with c-Kit mutant melanoma eventually progress on this inhibitor. We examined acquired resistance to imatinib and the newer generation inhibitor nilotinib in resistant c-kit mutant melanoma sublines. Four imatinib-resistant and six nilotinib-resistant sublines had acquired additional, secondary c-Kit mutations. The secondary A829P c-Kit mutation rendered cells resistant to imatinib, but did not suppress the activity of the tyrosine kinase inhibitors nilotinib and dasatinib. Sublines with an additional T670I c-Kit mutation showed resistance to imatinib, nilotinib and dasatinib, but responded to sunitinib. The concurrent inhibition of the MAPK and PI3K pathways was also effective at promoting apoptosis in the parent and derived resistant sublines. Our data provide a rationale for treating patients with melanoma progressing on imatinib or nilotinib with alternative RTK inhibitors or inhibitors targeting the MAPK and PI3K signalling cascades.

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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
KIT	A829P	missense	gain of function	KIT A829P lies within the protein kinase domain of the Kit protein (UniProt.org). A829P results in constitutive phosphorylation of Kit, activation of Akt and Erk signaling, and confers acquired resistance to imatinib in culture (PMID: 23582185).	Y

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