Combination Of Cetuximab And PP242 Synergistically Suppress The Progression Of Wild-type KRAS Colorectal Carcinoma

Background:Mammalian target of rapamycin complex 1 and 2(mTORC1/2)have been showed overactive in human colorectal cancer,but the first generation mTOR inhibitor,rapamycin,has failed to show clinical efficiency against colorectal cancer.On the other hand,although the second generation mTOR inhibitor,PP242,has exerted substantial efficiency,it was revealed that independent inhibition by PP242 was transient,which could led to positive feedback loop to EGFR.Objective:To investigate the efficiency of combinational therapy of PP242 and anti-EGFR MoAb against wild-KRAS colorectal carcinoma.Methods:Using wild-type KRAS colorectal cancer cells as models,we investigate the treatment efficiency of a widely used anti-EGFR MoAb,cetuximab,and PP242,alone or in combination in vitro and in vivo.Results:Results of cell viability assays confirmed the synergistic inhibitory effect of PP242 and cetuximab on the survival of CAC02 and HT-29 cells.Moreover,the ability of cancer cell invasion and proliferation was also significantly inhibited by the combinational therapy when compared with cetuximab or PP242 alone.Interestingly,the percentage of CD44 positive cancer cells was substantially decreased by the combinational therapy in comparison with PP242 alone through Fluorescence Activated Cell Sorter(FACS).The growth of cancer stem-like cell(CSC)spheres in vitro was also maximumly inhibited by combinational therapy,in terms of either diameter or number.More importantly,the efficiency of combinational therapy was more prominent than either drug alone in established tumor xenografts.Conclusion:These findings supported the potential use of combination therapy of PP242 and cetuximab against wild-type KRAS colorectal carcinomas.