In colorectal cancer diverse mutations of genes involved in signal transduction pathways for cell survival and proliferation areobserved, which have been the therapeutic targets for improvement of malignancies. The present study was undertaken toinvestigate whether NVP-BEZ235 (BEZ235), a dual inhibitor of PI3K/mTOR, shows any anti-proliferative effect on colorectal celllines harboring KRAS, and/or, PIK3CA, and/or BRAF mutations and to determine whether these mutational status affects thesensitivity of colorectal cancer cells to BEZ235. BEZ235 treatment induced growth inhibition in all four cell lines tested. HCT116cell line with both KRAS and PIK3CA mutation, and LoVo cell line with KRAS mutation showed higher IC50 values (643±19 nMand 663±7 nM, respectively) at 3 days post-treatment. On the other hand, HCT15 cell line harboring the same mutationalstatus as HCT116 with KRAS and PIK3CA mutation, and HT29 cell line with BRAF mutation were more sensitive to BEZ235 (IC50values; 25±7 nM and 213±40 nM, respectively). At suboptimal concentrations of BEZ235 (50 nM), HCT116 and LoVo cell lineswere less responsive comparing with the HCT15 and HT29 cell lines, whereas a higher doses of BEZ235 showed a similarresponse of growth inhibition in all four cell lines tested except HCT15. These studies provide the preclinical rationale forevaluating the efficacy of BEZ235.