Reversal of Mutant KRAS-Mediated Apoptosis Resistance by Concurrent Noxa/Bik Induction and Bcl-2/Bcl-xL Antagonism in Colon Cancer Cells

摘要: KRAS mutations are frequently detected in human colorectal cancer and contribute to de novo apoptosis resistance ultimately therapeutic failure. To overcome -mediated resistance, the irreversible proteasome inhibitor, carfilzomib, was evaluated found potently induce Noxa, which dependent upon c-Myc , Bik . Isogenic mutant versus wild-type carcinoma cells showed elevated Bcl-xL, confirmed by siRNA or ectopic expression. Upregulated Bcl-xL mediated ERK as indicated knockdown. expression regulated at level of mRNA protein shown using actinomycin D cyclohexamide, respectively. Suppression shRNA sensitized carfilzomib. Concurrent antagonism BH3 mimetic ABT-263 combined with carfilzomib synergistically enhanced that on Bax p53 attenuated Noxa shRNA. In support this strategy, ectopically expressed ABT-263. Carfilzomib-induced sequestered Mcl-1 released Bak from suggesting a mechanism for drug synergy. These preclinical findings establish upregulation key -mutant cancer. Furthermore, antagonizing enabled carfilzomib-induced synergistic reversed resistance. Implications: This novel study reveals promising treatment strategy concurrent Noxa/Bik Bcl-xL. Mol Cancer Res; 13(4); 659–69. ©2014 AACR