Abstract LB-208: Hijacking the PI3K/mTor and KRas/MEK/ERK signaling pathways with a therapeutic assault results in robust antitumor activity in PI3K/KRas and KRas mutant tumors
Authors: Vincent1 Loic , Thomas1 Anne , Ma2 Jianguo , Clark2 Anderson , Shaw2 Jamie , Guérif1 Stéphane , Egile1 Coumaran , Lager1 Joanne , Debussche1 Laurent , Lengauer1 Christoph , Garcia-Echeverria1 Carlos , Ogden2 Janet A. 
Published: August 2014

Abstract
The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK are interlinked growth and survival signaling pathways both involving regulation by Ras and often constitutively activated in human tumors as a result of frequent mutations in p1 10α, Ras and BRaf. Here, we have assessed the antitumor activity of the oral, potent and selective allosteric inhibitor of MEK1/2, MSC1936369 (formerly known as AS703026), in combination with SAR245408 (pan-PI3K formerly named XL147) or SAR245409 (dual panPI3K/mTOR formerly named XL765) in cellular in vitro and in vivo xenograft settings.
In vitro, the anti-proliferative effects of MSC1936369 in combination with SAR245409 were evaluated in a panel of 81 tumor cell lines (17 indications). Potent combination effects were seen in colorectal, pancreatic, breast and NSCL cancers when compared to each agent alone. Across indications, tumor cells harboring mutations in KRas, p1 10α, BRaf and both p1 10α and KRas were identified as those more sensitive to the combination.
In vivo, suboptimal therapeutic doses of MSC1936369, SAR245408 and SAR245409 were tested PO daily as single agents and in combination in human tumor xenograft models: MiaPaCa-2 pancreatic carcinoma (KRas mut), HCT116 colorectal adenocarcinoma (KRas/PIKC3A mut). In animals bearing MiaPaCa-2 xenografts, tumor growth inhibition was observed in all of the treatment groups, to varying degrees, compared to vehicle (p&lt;0.05) and the combination of MSC1936369 and SAR245409 induced a significantly enhanced anti-tumor activity as compared to single agent therapies. A trend for an enhanced antitumor effect of the combination with SAR245408 also emerged but was not significant. In animals bearing HCT 116 xenografts, single agent therapy with MSC1936369 was active, whereas SAR245408 and SAR245409 were inactive. Combination treatments induced a sustained tumor stasis with several partial regressions and demonstrated therapeutic synergy as compared to single agents (p&lt;0.05). Using primary colon xenografts (KRas mut or dual KRas/PIKC3A mut), the greatest activity was achieved with the KRas mutated tumor model followed by the dual KRas/PIKC3A mutated tumor.
Overall, the combination treatment of the MEK inhibitor MSC1936369 and the dual panPI3K/mTOR inhibitor SAR245409 showed enhanced tumor inhibition both in a large battery of tumor-derived cell lines as well as in xenograft models of human cancer (KRas mut and dual PI3K/KRas mut). In addition, combination therapy with the panPI3K inhibitor SAR245408 demonstrated a robust gain of antitumor activity, particularly in the dual PI3K/KRas mutant tumors. The available preclinical pharmacological data support the use of these combinations in clinical settings.
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-208. doi:10.1158/1538-7445.AM2011-LB-208