Abstract
BackgroundMitogen-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.MethodsWe 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.ResultsWe identified β-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in β-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.ConclusionsWe propose that inhibition of the WNT pathway, particularly β-catenin, may bypass resistance to MEK inhibition in human PIK3CA mt colon cancer. Therefore, we suggest that β-catenin is a potential predictive marker of MEK inhibitor resistance.
Highlights
Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy
Many MEK inhibitor-resistant cell lines harbour activating mutations in the phosphatidylinositol 3-kinase (PI3K) pathway, including PIK3CA.[9]. This has resulted in investigations into dual inhibition of the MEK and PI3K pathways; these combinations have been limited in their clinical usefulness due to significant toxicities
We demonstrate that MEK inhibitor sensitivity was driven by the PIK3CA genotype in KRAS mutant colon cancer cells
Summary
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. 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. 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, β-catenin, may bypass resistance to MEK inhibition in human PIK3CA mt colon cancer. Several studies have shown that the majority of MEK inhibitor-insensitive colon cancer cell lines harbour activating mutations in the PI3K pathway, whereas KRAS mutant cancer cells with an intact wild-type PI3K pathway are sensitive to MEK inhibitors.[9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
