Abstract LB-295: Combination of PI3K (SAR245408 and SAR245409) and MEK (MSC1936369B) inhibitors induce tumor apoptosis in vivo: fluorescence molecular tomography study in a human colon carcinoma xenograft model

The Merck-Serono MEK1/2 allosteric inhibitor MSC1936369B (formerly known as AS703026) was combined with the sanofi-aventis pan-PI3K inhibitor SAR245408 (also known as XL147) or the pan-PI3K/mTOR inhibitor SAR24540 (also know as XL765) in mice bearing colon carcinoma HCT116 xenograft tumors. These tumors harbor both KRAS (G13D) and PIK3CA (H1047R) mutations. Apoptosis induction was monitored non-invasively in vivo using fluorescence molecular tomography (FMT) after injection of fluorescent Annexin-V. Ex vivo apoptosis was assessed on tumor lysates using assays for cleaved caspase-3 and cleaved PARP detection. Suboptimal doses of SAR245408, SAR245409, and MSC1936369B were administered orally on a daily schedule as single agents or in combination. Single agent treatments showed marginal or no activity on HCT116 tumor growth inhibition. In contrast, robust enhanced anti-tumor activity was observed with the combination treatments, resulting in sustained tumor stasis and regression for both SAR245408/MSC1936369B (p in vivo by FMT was induced for the SAR245408/MSC1936369B combination, with p=0.005 and p In conclusion, the combination between the MEK1/2 inhibitor MSC1936369B with the pan-PI3K inhibitor SAR245408 or the pan-PI3K/mTOR SAR245409 resulted in significantly enhanced anti-tumor activity in a KRAS/PIK3CA mutated tumor xenograft model, with synergistic induction of tumor apoptosis as demonstrated ex vivo for both combinations and in vivo using longitudinal FMT imaging for the SAR245408/MSC1936369B combination. 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 LB-295. doi:10.1158/1538-7445.AM2011-LB-295