PDGFR/FYN/c-MYC axis confers dual resistance to MEKi and PI3K/mTORi in colorectal cancer

Target therapy is a fundamental treatment for colorectal cancer (CRC), while drug resistance dramatically limited the clinical application. Combination of MEKi and PI3K/mTORi was a promising strategy for single agent resistant CRC, however, dual drug resistance was inevitably occur from the long term experience. In this study, we prospectively explore the mechanism underlying dual resistance to MEKi and PI3K/mTORi in CRC. We established dual-polyclonal resistant (DPR) cells to MEKi and PI3K/mTORi and validated compensatory pathways involved in the process of acquired resistance. We performed transcriptome profiling and identified focal adhesion pathways were significantly enriched during dual resistance. c-MYC was significantly upregulated in DPR cells. Knockdown c-MYC arrested cell cycle and downregulated cell cycle related proteins, such as CDK4, CDK8, and cyclin D1. Overexpression of c-MYC significantly promoted proliferation of DPR cells. FYN functioned as upstream target of c-MYC, knockdown of FYN downregulated expression of c-MYC. Knockdown of FYN and family member small molecule inhibitor administration significantly inhibited proliferation of HCT116 and HT29 DPR cells. Co-IP confirmed the directly interaction of FYN and c-MYC. PDGFR downregulated phosphonate of FYN and c-MYC. Our results identified PDGFR/FYN/c-MYC axis mediated dual resistance to MEKi and PI3K/mTORi, which may be applied in explore novel druggable targets for CRC treatment. Moreover, our results provided novel combinational strategy for relapsed CRC, which may improve the survival outcome of patient with CRC.