Targeting the PI3K signaling pathway in KRAS mutant colon cancer
- Authors
- Hong, Suntaek; Kim, SoYoung; Kim, Hye Youn; Kang, Myunghee; Jang, Ho Hee; Lee, Won-Suk
- Issue Date
- Feb-2016
- Publisher
- WILEY
- Keywords
- BKM120; colon cancer; combination therapy; KRAS; PIK3CA
- Citation
- CANCER MEDICINE, v.5, no.2, pp.248 - 255
- Journal Title
- CANCER MEDICINE
- Volume
- 5
- Number
- 2
- Start Page
- 248
- End Page
- 255
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/8609
- DOI
- 10.1002/cam4.591
- ISSN
- 2045-7634
- 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 1mol/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.
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