Phosphoinositide 3-Kinase Inhibitors Combined with Imatinib in Patient-Derived Xenograft Models of Gastrointestinal Stromal Tumors: Rationale and Efficacy
| Autor: | Paul W. Manley, Jonathan A. Fletcher, Raf Sciot, Patrick Schöffski, Ulla Vanleeuw, Maria Debiec-Rychter, Thomas Van Looy, Haifu Li, Giuseppe Floris, Agnieszka Wozniak, Jasmien Wellens |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Gastrointestinal Stromal Tumors Mitosis Antineoplastic Agents Apoptosis Pharmacology Piperazines Mice In vivo Animals Humans Medicine PTEN Stromal tumor Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors GiST biology business.industry PTEN Phosphohydrolase Cancer Imatinib medicine.disease Xenograft Model Antitumor Assays Tumor Burden Disease Models Animal Proto-Oncogene Proteins c-kit Pyrimidines Imatinib mesylate Oncology Benzamides Imatinib Mesylate biology.protein Cancer research Drug Therapy Combination Female business Signal Transduction medicine.drug |
| Zdroj: | Clinical Cancer Research. 20:6071-6082 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Introduction: The PI3K signaling pathway drives tumor cell proliferation and survival in gastrointestinal stromal tumor (GIST). We tested the in vivo efficacy of three PI3K inhibitors (PI3Ki) in patient-derived GIST xenograft models. Experimental Design: One hundred and sixty-eight nude mice were grafted with human GIST carrying diverse KIT genotypes and PTEN genomic status. Animals were dosed orally for two weeks as follows: control group (untreated); imatinib (IMA); PI3Ki (BKM120—buparlisib, BEZ235, or BYL719) or combinations of imatinib with a PI3Ki. Western blotting, histopathology, and tumor volume evolution were used for the assessment of treatment efficacy. Furthermore, tumor regrowth was evaluated for three weeks after treatment cessation. Results: PI3Ki monotherapy showed a significant antitumor effect, reflected in tumor volume reduction or stabilization, inhibitory effects on mitotic activity, and PI3K signaling inhibition. The IMA+PI3Ki combination remarkably improved the efficacy of either single-agent treatment with more pronounced tumor volume reduction and enhanced proapoptotic effects over either single agent. Response to IMA+PI3Ki was found to depend on the KIT genotype and specific model-related molecular characteristics. Conclusion: IMA+PI3Ki has significant antitumor efficacy in GIST xenografts as compared with single-agent treatment, resulting in more prominent tumor volume reduction and enhanced induction of apoptosis. Categorization of GIST based on KIT genotype and PI3K/PTEN genomic status combined with dose optimization is suggested for patient selection for clinical trials exploring such combinations. Clin Cancer Res; 20(23); 6071–82. ©2014 AACR. |
| Databáze: | OpenAIRE |
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