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|Ref Type||Journal Article|
|Authors||Cullinane C, Natoli A, Hui Y, Conus N, Jackson S, Bruggen J, Manley PW, McArthur GA|
|Title||Preclinical evaluation of nilotinib efficacy in an imatinib-resistant KIT-driven tumor model.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||The novel KIT inhibitor nilotinib is currently being evaluated for its clinical utility in the treatment of gastrointestinal stromal tumor. However, the effects of nilotinib in cells expressing commonly occurring KIT mutations remain to be fully defined. The aim of this study was therefore to investigate the efficacy of nilotinib against cells expressing imatinib-sensitive or imatinib-resistant KIT mutations and to evaluate [(18)F] fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging as a biomarker of nilotinib response in vivo. Nilotinib inhibited the proliferation of imatinib-responsive V560G-KIT FDC-P1 and imatinib-resistant D816V-KIT FDC-P1 cells with a GI(50) of 4.9 and 630 nmol/L, respectively, whereas apoptosis studies revealed that nilotinib and imatinib were equipotent against the V560G cell line. In contrast, although 10 micromol/L nilotinib induced >50% apoptosis in the D816V cells at 16 hours, 10 micromol/L imatinib had no effect on cell survival at 24 hours. Syngeneic DBA2/J mice bearing FDC-P1-KIT tumors were evaluated for response to nilotinib by FDG-PET. V560G-KIT FDC-P1 tumor FDG uptake was significantly reduced compared with baseline levels following 2 days of nilotinib treatment. In contrast, no effect of nilotinib was observed on tumor growth or FDG-PET uptake into D816V tumors despite intratumoral drug levels reaching in excess of 10 micromol/L at 4 hours after dosing. Biomarker analysis revealed the inhibition of KIT phosphorylation in V560G but not D816V tumors. These findings show the in vivo activity of nilotinib in the treatment of tumors bearing V560G-KIT but not D816V-KIT and the utility of FDG-PET imaging to assess tumor response to this agent.|
|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 D816V||Advanced Solid Tumor||decreased response||Nilotinib||Preclinical||Actionable||In a preclinical study, Tasigna (nilotinib) decreased viability of cells expressing KIT D816V in culture, but did not inhibit KIT phosphorylation or growth of KIT D816V-expressing tumors in mouse models (PMID: 20442311).||20442311|
|KIT V560G||Advanced Solid Tumor||sensitive||Nilotinib||Preclinical||Actionable||In a preclinical study, transformed cells expressing KIT V560G demonstrated inhibition of cell proliferation and tumor regression both in culture and in vivo when treated with Tasigna (nilotinib) (PMID: 20442311).||20442311|