Abstract 1632: Co-targeting mTOR and IGF-1R/IR results in synergistic activity against a broad array of tumor cell lines, independent of KRAS mutation status

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The IGF-1 receptor (IGF-1R) and insulin receptor (IR) are known to couple via IRS-1 to the PI3K signaling axis. Upon activation, these receptor tyrosine kinases stimulate PI3K, initiating a cascade of ser/thr kinases, including mTOR. mTOR is associated with two complexes: mTORC1, rapamycin sensitive, and mTORC2, which does not bind rapamycin. Since mTOR functions downstream of IGF-1R and IR, it is thought that tumor cells sensitive to IGF-1R inhibition would also respond to mTORC1/mTORC2 inhibition. To test this hypothesis we evaluated the effects of OSI-906, a selective small molecule dual kinase inhibitor of IGF-1R and IR and OSI-027, a selective catalytic-site inhibitor of mTORC1/mTORC2, alone and in combination in cell proliferation assays using a broad array of tumor cell lines. Across multiple tumor types, cells with activating KRAS mutations were typically less sensitive to OSI-027 than those expressing wild-type KRAS. In contrast, mutant KRAS did not reduce sensitivity to OSI-906. Cell lines with activating mutations in PIK3CA or loss of PTEN were sensitive to OSI-027 but the presence of a concurrent mutation in KRAS decreased their sensitivity to OSI-027. In KRAS mutant cells, OSI-906 was more effective than OSI-027 at reducing phospho-AKT levels. Conversely, in tumor cell lines with wild-type KRAS cells, OSI-027 more effectively reduced phospho-AKT levels compared to OSI-906. Similar effects were observed in a pair of isogenic cell lines engineered to express either wild-type or mutant KRAS. The observation that tumor cell lines exhibit differential sensitivity to inhibitors of IGF-1R/IR or mTORC1/mTORC2 supports the concept that IGF-1R and IR can activate multiple pathways and are not limited to signaling through the mTOR axis. Also, mTOR is a central signaling hub which integrates signaling from multiple inputs, not only the IGF-1R/IR cascade. The combination of OSI-906 and OSI-027 synergistically inhibited the proliferation of cancer cell lines, including those expressing mutant KRAS. In some cases, the combination also resulted in synergistic induction of apoptosis. These data provide support for further exploration of the potential utility of combining OSI-906 (dual IGF-1R/IR inhibitor) with OSI-027 (dual mTORC1/mTORC2 inhibitor) for the treatment of human cancers, including those with activating mutations in KRAS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1632.