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Updated: Jun 13, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Preclinical evaluation of nilotinib efficacy in an imatinib-resistant KIT-driven tumor model
Carleen Cullinane1, Anthony Natoli, Yorlon Hui
1Translational Research Laboratory, Research Division, East Melbourne, Victoria, Australia.
Abstract:
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.
Insights
Nilotinib effectively treats gastrointestinal stromal tumors with V560G-KIT mutations but not D816V-KIT mutations. [(18)F] fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging can assess nilotinib response in vivo.
Area of Science:
- Oncology
- Pharmacology
- Medical Imaging
Background:
- Gastrointestinal stromal tumors (GIST) often harbor KIT mutations.
- Nilotinib is a novel KIT inhibitor being investigated for GIST treatment.
- The efficacy of nilotinib against specific KIT mutations and its in vivo response biomarkers require further definition.
Purpose of the Study:
- To investigate the efficacy of nilotinib against KIT mutations common in GIST.
- To evaluate [(18)F] fluorodeoxyglucose-positron emission tomography (FDG-PET) as a biomarker for nilotinib response.
- To compare nilotinib's activity against imatinib-sensitive (V560G-KIT) and imatinib-resistant (D816V-KIT) mutations.
Main Methods:
- Cell proliferation and apoptosis assays were performed using FDC-P1 cells expressing V560G-KIT and D816V-KIT.
- In vivo studies utilized syngeneic DBA2/J mice bearing FDC-P1-KIT tumors.
- Tumor response was assessed using FDG-PET imaging and biomarker analysis of KIT phosphorylation.
Main Results:
- Nilotinib inhibited proliferation and induced apoptosis in V560G-KIT cells, showing equipotent activity with imatinib.
- Nilotinib induced apoptosis in D816V-KIT cells, while imatinib had no significant effect.
- In vivo, nilotinib reduced FDG uptake in V560G-KIT tumors but not in D816V-KIT tumors.
- Biomarker analysis confirmed KIT phosphorylation inhibition in V560G-KIT tumors but not in D816V-KIT tumors.
Conclusions:
- Nilotinib demonstrates in vivo efficacy against tumors with V560G-KIT mutations.
- Nilotinib is ineffective against tumors with D816V-KIT mutations.
- FDG-PET imaging serves as a useful biomarker for assessing tumor response to nilotinib therapy.
