Journal
BRITISH JOURNAL OF CANCER
Volume 120, Issue 9, Pages 941-951Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41416-019-0434-5
Keywords
-
Categories
Funding
- Ministry of Health and Welfare and Family Affairs [A110708]
- National Research Foundation of Korea (NRF) - Korea government (MEST) [2013R1A2A2A01067394]
- National Research Foundation (NRF) - Ministry of Science & ICT, Republic of Korea [NRF-2017R1A2B4012721]
- National Research Foundation of Korea [2013R1A2A2A01067394] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Ask authors/readers for more resources
BACKGROUND: Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in KRAS mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients. METHODS: We investigated a biomarker of response for MEK inhibition in KRAS mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in PIK3CA wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo. RESULTS: We identified beta-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in beta-catenin in PIK3CA wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing PIK3CA wt. CONCLUSIONS: We propose that inhibition of the WNT pathway, particularly beta-catenin, may bypass resistance to MEK inhibition in human PIK3CA mt colon cancer. Therefore, we suggest that beta-catenin is a potential predictive marker of MEK inhibitor resistance.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available