HDAC Inhibition Overcomes Acute Resistance to MEK Inhibition in BRAF-Mutant Colorectal Cancer by Downregulation of c-FLIPL

摘要: Purpose: Activating mutations in the BRAF oncogene are found 8-15% of colorectal cancer (CRC) patients and have been associated with poor survival. In contrast to mutant (MT) melanoma, inhibition MAPK pathway is ineffective majority BRAFMT CRC patients. Therefore, identification novel therapies for urgently needed. Experimental Design: WT models were assessed vitro vivo. Small molecule inhibitors MEK1/2, MET HDAC employed, over-expression siRNA approaches applied, cell death was by flow cytometry, Western blotting, viability caspase activity assays. Results: Increased c-MET-STAT3 signalling identified as a adaptive resistance mechanism MEK (MEKi) Moreover, MEKi treatment resulted acute increases transcription endogenous caspase-8 inhibitor c-FLIPL cells, but not BRAFWT STAT3 abrogated MEKi-induced expression. addition, c-FLIP-specific or upregulation expression significant cells. Notably, combined inhibitor/MEKi dramatically attenuated tumor growth xenografts. Conclusions: Our findings indicate that c-MET/STAT3-dependent an important escape following CRC. Thus, combinations c-MET c-FLIP (eg. inhibitors) could be potential strategies