Abstract 4480: Combination of a PI3K/mTOR inhibitor and a MEK inhibitor at suboptimal dose significantly inhibits growth of lung adenocarcinoma tumors in KrasG12D-LSL mice

Abstract

Abstract The KrasG12D-LSL conditional GEMMs (genetically engineered mouse models) are a valuable tool in translational research to study tumor progression and to investigate efficacy of anti-tumor compounds in a variety of cancer types. Here, intranasal delivery of adeno-Cre resulted in the expression of mutant Kras leading to development of tumor lesions in the lungs including adenomatous hyperplasia, large adenoma and adenocarcinoma. Treatment of tumor bearing mice at adenocarcinoma stage (at 14 weeks post adeno-cre inhalation) with suboptimal dose of PF-04691502 (PI3Ka/mTOR inhibitor; 7.5 mg/kg; SID) and PD-0325901 (MEK inhibitor, 1.5 mg/kg; SID) reduced tumor lesions in mice treated with single agents and significantly inhibited tumor growth in mice treated with combination of both compounds. In addition, immunohistochemistry showed inhibition of pS6 in the treated animals particularly in the combination group providing a proof of mechanism for the tumor growth inhibition. Similar response was observed when mice bearing H460 (carry Kras and PIK3CA mutations) orthotopic lung tumors were treated with the combination regimen. These observations provide some clue to further pursue efficacy of PF-04691502 plus PD-0325901 in the clinical settings and also in more invasive models such as KrasG12D-LSLp53flox/flox mice. 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 4480. doi:10.1158/1538-7445.AM2011-4480