A combinatorial strategy for overcoming primary and acquired resistance of MEK inhibition in colorectal cancer

Compared with traditional chemotherapeutic drugs, targeted therapeutic medicine has the advantages of high efficacy and less toxic side effects. However, in clinical practice for treatment of colorectal cancer, the primary and acquired resistance of these medicines limits their effectiveness in targeted therapy, therefore impedes the development of precision medicine and personalized therapy. Currently, there are limited number of drugs for targeted therapy of colorectal cancer, mainly monoclonal antibodies against EGFR or VEGFR inhibitors. Trametinib, a MEK inhibitor, has been applied in melanoma patient successfully, but not been used in clinical treatment of colorectal cancer because of its drug resistance. To identify the resistance mechanism of colorectal cancer cells to trametinib and find useful chemical combination to overcome the resistance, we screened primary and acquired cell line first and then tested multiple synergistic drug combinations by using the Chou-Talalay method. We obtained the primary resistant cell lines SW480, CW-2 and the acquired drug-resistant cell line RKO-R as well as a synergistic combination of trametinib and GSK2126458. This combination inhibits the colony formation of colorectal cancer cells and the growth of xenograft tumors in nude mice. Mechanistic analysis showed that trametinib can activate the alternative PI3K-AKT signaling pathway while inhibiting the MAPK pathway, which may be one of the molecular mechanisms of primary and acquired trametinib tolerance in colorectal cancer cells. Importantly, this bypass activation can be blocked by GSK2126458. These results suggest that a combination of trametinib and GSK2126458 is an effective approach for treating colorectal cancer resistance to trametinib.