Combination Of Rapamycin With Sorafenib As A Therapeutic Strategy Against Colorectal Cancers With Mutational Activation Of Kras And Pik3ca

Both PI3K/Akt/mTOR and Ras/Raf/ERK (MAPK) signaling pathways are constitutively activated and serve critical functions in the growth of colorectal cancer (CRC). Rapamycin inhibits the kinase activity of mTORC1 but leads to feedback activation of Akt, resulting in cell survival and chemoresistance. Sorafenib is a multikinase inhibitor that inhibits Raf kinase and subsequently MAPK signaling. Recent studies suggest that inhibition of mTORC1 with rapamycin leads to feedback induction of MAPK signaling through a S6K-PI3K-Ras feedback loop. Therefore, we investigated whether combination of rapamycin with sorafenib has therapeutic benefit in CRC. METHODS. HCT116 and DLD-1 human CRC cells (mutant K-RAS and PIK3CA) were treated with either rapamycin (50 nM) or sorafenib (5 µM) alone or in combination. Effects on cell proliferation (measured by cell counting), apoptosis (measured by detecting levels of histone-associated DNA fragments in mono- and oligonucleosomes) and subcutaneous growth in athymic nude mice were analyzed. RESULTS. (i) pAkt Ser473 and pERK Thr202/Tyr204 are overexpressed together in stage IV CRC tissues and in matched liver metastasis tissues from the same patient (Spearman9s correlation=0.77; p 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 1963. doi:10.1158/1538-7445.AM2011-1963