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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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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 |
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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 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 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 | 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 |