title: Targeting the PI3K signaling pathway in KRAS mutant colon cancer.
abstract: 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.
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Suntaek
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Surgery, Gil Medical Center, Gachon University, Incheon, Korea.|Gachon Medical Research Institute, Gil Medical Center, Incheon, Korea.
authors.forename: SoYoung
authors.initials: S
authors.lastname: Kim
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Hye Youn
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Pathology, Gil Medical Center, Gachon University, Incheon, Korea.
authors.forename: Myunghee
authors.initials: M
authors.lastname: Kang
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.|Gachon Medical Research Institute, Gil Medical Center, Incheon, Korea.
authors.forename: Ho Hee
authors.initials: HH
authors.lastname: Jang
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.|Department of Surgery, Gil Medical Center, Gachon University, Incheon, Korea.|Gachon Medical Research Institute, Gil Medical Center, Incheon, Korea.
authors.forename: Won-Suk
authors.initials: WS
authors.lastname: Lee
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D053148:Caspase 3; D000068818:Cetuximab; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins; C571178:NVP-BKM120
keywords: BKM120; KRAS; PIK3CA; colon cancer; combination therapy