To examine the therapeutic potential of the mTOR kinase inhibitor PP242, we show here that PP242 can only transiently block the mTORC2 kinase activity in the first few hours of the treatment. In parallel, the return of mTORC2 kinase activity is associated with the increase of phosphorylated EGFR. The combination treatment of PP242 and erlotinib, an EGFR inhibitor, completely block both mTORC1 and mTORC2 activity, inhibits cell growth and suppresses the progression of colorectal carcinoma xenografts. Cells in single-cell suspension were plated and grown in 6- wells plates at a density of 1000 cells per well for 24 hours. Cells were then treated or untreated with PP242 and erlotinib, alone or combination. The medium was replaced every 4 days with fresh medium LY2835219 containing PP242 and/or erlotinib. After 14 days, the medium was removed and cell colonies were stained with 0.5% crystal violet solution. The expression of mTOR, RACTOR, RICTOR, p70S6K and 4E-BP1 is elevated in colorectal carcinoma. Because mTORC2 phosphorylates AKT at S473, we thought to identify the AKTS473 and determine whether the mTORC2 are activated in the carcinoma. Western blotting revealed that AKTS473 were elevated in the carcinoma tissues as compared with the matched normal tissues, thus suggesting the activation of mTORC2 in the carcinomas; however, non-phosphorylated AKT was also elevated, which could not rule out the possibility that the overexpression might cause the phosphorylation in the cancer tissues. During the activation of mTORC1, its substrate p70S6K phosphorylates ribosomal protein S6. The expression of S6 protein was consistent in matched carcinoma and normal tissues, but detection of the phosphorylated S6 at S235/236 in the carcinoma but not matched normal tissues suggested the elevated mTORC1 activity in the Wortmannin carcinomas. To determine whether the mTOR kinase inhibitor PP242 block mTORC1 and mTORC2 kinase activity in the carcinoma cells, we first examined a panel of eight carcinoma cell lines for the response to PP242 and showed that PP242 treatment inhibited the growth of each cell line in a dose-dependent manner. Next, we examined the phosphorylated S6S235/236 and 4E-BP1 at T36/45 and the mTORC2 substrate AKTS473 in the cells after PP242 treatment at the high dose of 1 ��M. Western blotting showed that PP242 treatment at the high dose completely abolished the S6S235/236 but partially reduced the 4E-BP1T36/45, consistent with the earlier report that PP242 incompletely inhibits 4E-BP1 phosphorylation.