Oncogenic KIT signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor

Department of Developmental Biology, Computational Biology Center, and Molecular Cytology Facility, Sloan-Kettering Institute, New York, NY 10021, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2006; 103(34):12843-8. DOI: 10.1073/pnas.0511076103
Source: PubMed


Kit receptor-activating mutations are critical in the pathogenesis of gastrointestinal stromal tumors (GIST). We investigated mechanisms of oncogenic Kit signaling and the consequences of therapeutic intervention in a mouse model of human GIST. Treatment of GIST mice with imatinib decreased cell proliferation and increased apoptosis in the tumor. Analysis of tumor tissue from imatinib-treated mice showed diminished phosphatidylinositol 3-kinase (PI3-kinase) and mammalian target of rapamycin (mTOR) signaling suggesting that oncogenic Kit signaling critically contributes to the translational response in GIST. Treatment with RAD001 (everolimus), an mTOR inhibitor, diminished the translational response and cell proliferation in tumor lesions, pointing to mTOR inhibition as a therapeutic approach for imatinib-resistant GIST. Analysis of RNA expression profiles in GIST lesions with and without imatinib treatment showed changes in expression of IFN-inducible genes and cell cycle regulators. These results convincingly show that KitV558Delta/+ mice represent a unique faithful mouse model of human familial GIST, and they demonstrate the utility of these mice for preclinical investigations and to elucidate oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention.

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    • ". In addition, we have also added to the grading system the area with myxoid degeneration, which is characterized by the replacement of viable tumor tissue by an amorphous matrix with low cellularity as a pattern of response to TKI treatment observed [21]. Mitotic figures and apoptotic cells were counted in 10 high power fields (0.45-mm field diameter) at × 400 magnification on H&E staining. "
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    ABSTRACT: We evaluated the efficacy of CK6, a KIT monoclonal antibody, in a panel of human gastrointestinal stromal tumor (GIST) xenograft models. Nude mice were bilaterally transplanted with human GIST xenografts (four patient derived and two cell line derived), treated for 3 weeks, and grouped as follows: control (untreated); CK6 (40 mg/kg, 3× weekly); imatinib (50 mg/kg, twice daily); sunitinib (40 mg/kg, once daily); imatinib + CK6; sunitinib + CK6 (same doses and schedules as in the single-agent treatments). Tumor volume assessment, Western blot analysis, and histopathology were used for evaluation of efficacy. Statistical analysis was performed using Mann-Whitney U (MWU) and Wilcoxon matched-pairs tests. CK6 as a single agent only reduced tumor growth rate in the UZLX-GIST3 model (P = .053, MWU compared to control), while in none of the other GIST models an effect on tumor growth rate was observed. CK6 did not result in significant anti-proliferative or pro-apoptotic effects in any of the GIST models, and moreover, CK6 did not induce a remarkable inhibition of KIT activation. Furthermore, no synergistic effect of combining CK6 with tyrosine kinase inhibitors (TKIs) was observed. Conversely, in certain GIST xenografts, anti-tumor effects seemed to be inferior under combination treatment compared to single-agent TKI treatment. In the GIST xenografts tested, the anti-tumor efficacy of CK6 was limited. No synergy was observed on combination of CK6 with TKIs in these GIST models. Our findings highlight the importance of using relevant in vivo human tumor xenograft models in the preclinical assessment of drug combination strategies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Translational oncology 04/2015; 369(2). DOI:10.1016/j.tranon.2015.02.004 · 2.88 Impact Factor
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    • "Long-term drug resistance requires secondary mutations to be present in cells that are long-lived or able to self-renew 13. KIT is known to have anti-apoptotic activity, thus contributing to cell lifespan 14. Alternatively, resistance could arise from mutations in rare cells possessing stem cell attributes. "
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    ABSTRACT: Background: Most patients with advanced gastrointestinal stromal tumors (GIST) develop drug resistance to tyrosine kinase inhibitors (TKIs) within two years of starting therapy, whereas most chronic myeloid leukemia (CML) patients in chronic phase still exhibit disease control after a decade on therapy. This article aims to explain this divergence in long term outcomes. Methods and results: By combining clinical and experimental observations with mathematical formulas we estimate that, in advanced GIST, the genetic changes responsible for resistance are generally already present at disease detection. Conclusion: This result has relevant clinical implications by providing support for the exploration of combination therapies.
    F1000 Research 07/2013; 2:152. DOI:10.12688/f1000research.2-152.v1
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    • "Kit and PDGFRα oncoproteins activate signaling pathways, resulting in GIST cell proliferation and survival. In addition to ligand-independent constitutive Kit phosphorylation, GISTs harboring Kit mutations show activation of Kit downstream signaling pathways, including the PI3K/Akt, MAPK (Raf/Mek/Erk), and signal transducer and activator of transcription (STAT) pathways[10],[77]. Of these downstream signaling targets, MAPK phosphorylation is Kit-dependent, whereas phosphorylation of PI3K, STAT1, and STAT3 are partially Kit-dependent. "
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    ABSTRACT: Over the past 60 years, investigators of basic science, pathology, and clinical medicine have studied gastrointestinal stromal tumor (GIST) and made minor advances in patient care. Recent discoveries have led to an understanding of the biological role of KIT and platelet-derived growth factor receptor-α in GIST and the development of the tyrosine kinase inhibitor imatinib mesylate (Gleevec, formerly STI-571), one of the most exciting examples of targeted therapy to date. The success of targeted therapy in GIST has lead to new developments in our understanding of the medical and surgical management of the disease. Intense study of GIST may lead to new paradigms in the management of cancer.
    Chinese journal of cancer 05/2011; 30(5):303-14. DOI:10.5732/cjc.011.10062 · 2.16 Impact Factor
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