Title: Phosphoinositide 3-kinase inhibitors combined with imatinib in patient-derived xenograft models of gastrointestinal stromal tumours: rationale and efficacy
Authors: Van Looy, Thomas *
Wozniak, Agnieszka *
Floris, Beppe
Sciot, Raf
Li, Haifu
Wellens, Jasmien
Ulla, Vanleeuw
Fletcher, Jonathan A
Manley, Paul W
Debiec-Rychter, Maria
Sch√∂ffski, Patrick # ×
Issue Date: Dec-2014
Series Title: Clinical Cancer Research vol:20 issue:23 pages:6071-82
Article number: clincanres.1823.2014
Abstract: Purpose: PI3K signalling pathway drives tumour cell proliferation and survival in gastrointestinal stromal tumour (GIST). We tested the in vivo efficacy of three PI3K inhibitors (PI3Kis) in patient-derived GIST xenograft models. Experimental Design: 168 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 IMA with a PI3Ki. Western blotting, histopathology and tumour volume evolution were used for the assessment of treatment efficacy. Furthermore, tumour regrowth was evaluated for three weeks after treatment cessation. Results: PI3Ki monotherapy showed a significant anti-tumour effect, reflected in tumour volume reduction or stabilization, inhibitory effects on mitotic activity and PI3K signalling inhibition. The IMA+PI3Ki combination remarkably improved the efficacy of either single agent treatment with more pronounced tumour volume reduction and enhanced pro-apoptotic effects over either single agent. Response to IMA+PI3Ki was found to depend on the KIT genotype and specific model-related molecular characteristics. Conclusions: IMA+PI3Ki has significant anti-tumour efficacy in GIST xenografts as compared to single agent treatment, resulting in more prominent tumour 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.
ISSN: 1078-0432
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Experimental Oncology
Translational Cell & Tissue Research
Laboratory for Genetics of Malignant Disorders
* (joint) first author
× corresponding author
# (joint) last author

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