title: Phosphoinositide 3-kinase inhibitors combined with imatinib in patient-derived xenograft models of gastrointestinal stromal tumors: rationale and efficacy.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Looy
authors.affiliation: Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.affiliation: Department of Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Floris
authors.affiliation: Department of Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.affiliation: Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Haifu
authors.initials: H
authors.lastname: Li
authors.affiliation: Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Jasmien
authors.initials: J
authors.lastname: Wellens
authors.affiliation: Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vanleeuw
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.affiliation: Department of Human Genetics, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.affiliation: Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. patrick.schoffski@uzleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D051059:PTEN Phosphohydrolase