Reference Detail

Ref Type

Journal Article

PMID

(20442311)

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	9	5	2010 May	1461-8	Mol Cancer Ther

URL

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.

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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 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
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