buparlisib and Colonic-Neoplasms

Topics: Aminopyridines; Animals; Biomarkers, Tumor; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; HCT116 Cells; Humans; Mice; Morpholines; Phosphoinositide-3 Kinase Inhibitors; RNA Interference; RNA-Seq; S Phase; Transcription Factor AP-2; Xenograft Model Antitumor Assays

Metastatic colorectal cancer (CRC) patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to monoclonal antibody that targets the epidermal growth factor receptor such as cetuximab. BKM120 targets phosphatidylinositide-3-kinase (PIK3CA), but it is unknown whether BKM120 can reverse cetuximab resistance in KRAS mutant CRC. Human CRC cell lines with KRAS mutations (DLD-1, HCT116, and LoVo) were used to test the effect of cetuximab, BKM120, and cetuximab plus BKM120 on cell proliferation in vitro and in vivo. BKM120 reduced cell proliferation in a concentration-dependent manner in the LoVo (PI3KCA wild type) as well as the HCT116 and DLD1 cells (that carry a PI3KCA mutation). BKM120 only inhibited ERK phosphorylation in LoVo cells (PIK3CA wild type), but not in DLD1 or HCT116 cells at a concentration of 1 μmol/L. Treatment with cetuximab and BKM120 significantly reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone (P = 0.034). BKM120 may overcome cetuximab resistance in colon cancer cells with KRAS mutation.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cetuximab; Colonic Neoplasms; Disease Models, Animal; Drug Synergism; Humans; Male; MAP Kinase Signaling System; Molecular Targeted Therapy; Morpholines; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; ras Proteins; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays