Abstract 4495: Treatment effects of the novel mTOR kinase inhibitor AZD8055 in prostate cancer cell models

Abstract

Abstract The mTOR pathway is frequently hyperactivated in prostate cancer due to PTEN loss of function, hence rendering prostate cancer cells sensitive to mTOR inhibitors. Although the classic allosteric mTOR inhibitor rapamycin has shown considerable preclinical efficacy, clinical results suggest that rapamycin alone is insufficient to inhibit tumor growth in prostate cancer patients. AZD8055 is an ATP-competitive mTOR kinase inhibitor that efficiently blocks activation of both mTOR complex (mTORC) 1 and 2. In this study we evaluated the effects of AZD8055 in prostate cancer cell models. Cell proliferation after drug treatment was determined by MTT assay and cell cycle was analyzed using propidium iodide staining followed by flow cytometry. Protein expression was detected by Western blot. In both PC-3 (PTEN null) and DU145 (PTEN wildtype) cells, AZD8055 suppressed cell proliferation at the nanomolar level in a dose dependent manner. At the same concentration (100 nM), AZD8055 induced greater G1 phase arrest than rapamycin and the expression of proteins related to G1 progression (cyclin D1, c-Myc) was significantly decreased by AZD8055 while only slightly reduced by rapamycin. Mechanistically, although both drugs blocked phosphorylation of mTORC1 downstream targets S6K and S6, only AZD8055 inhibited phosphorylation of 4E-BP1, another mTORC1 downstream molecule, and Akt, a typical target of mTORC2. Importantly, cells that were able to survive and proliferate under rapamycin (100 nM) selective pressure remained responsive to AZD8055, even at the lowest dose (10 nM). Furthermore in a PC-3 cell line established to be highly resistant to rapamycin (PC-3RR), AZD8055 could still potently decrease cell proliferation, with an IC50 of 0.5 nM. Taken together, these findings indicate that a) AZD8055 is superior to rapamycin in growth inhibition of prostate cancer cells irrespective of PTEN status, b) AZD8055 is able to deactivate rapamycin-insensitive complexes involved in the mTOR signaling, and c) AZD8055 treatment can overcome rapamycin treatment-associated resistance. In summary, the novel mTOR kinase inhibitor AZD8055 may have significant therapeutic potential in prostate cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4495. doi:10.1158/1538-7445.AM2011-4495