Abstract 653: Combination of TORC1/2 and MEK kinase inhibitors in colorectal cancer models

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Abstract MAPK pathway mutations are frequent in colorectal cancer (CRC) and associated with resistance to standard therapies. This provides a rationale for the use of targeted therapies against the MAPK pathway. However, the response of CRC cells to MEK inhibitors varies depending on coexisting mutations in both MAPK and PI3K pathways. As a matter of fact, dual inhibition of MEK and PI3K or AKT in mouse models of CRC has proven effective due to aberrations in both pathways. Inhibition of TORC1, a shared downstream effector of the MAPK and PI3K pathways, was described to be partly responsible for the efficacy of the dual blockade. In order to explore additional mechanisms involved in the superior antitumor activity of combined MAPK and PI3K pathway suppression we directly targeted TORC1/2 by active-site kinase inhibitor of mTOR, in addition to MEK, in our cell models. We tested the antiproliferative activity of INK128, a selective and potent TORC1/2 inhibitor, in combination with a MEK inhibitor, PD-0325901, in a panel of colon cancer cell lines with diverse alterations of the MAPK and PI3K pathways. PD-0325901 treatment effectively inhibited ERK phosphorylation, which resulted in decreased phosphorylation of Rb and reduced expression of E2F in all the cell lines tested. In CRC cell lines harboring sole mutations in the MAPK pathway, we observed sensitivity to PD-0325901 that was not further enhanced when combining with INK-128. In contrast, CRC cell lines harboring concurrent mutations of both pathways exhibited a striking sensitivity to dual ERK and TORC1/2 blockade associated with an enhanced arrest in cell cycle and, above all, a concomitant increase in apoptosis. Inhibition of TORC1 and TORC2 by INK128 could not be further enhanced by MEK inhibition in any of the cell lines tested. These data suggest that, besides complete suppression of both pathways, additional mechanisms must be at work to explain the observed enhanced cell death following dual suppression of PI3K and MEK. Interestingly, we observed differential regulation of key components of the cell cycle in response to dual blockade. We are currently investigating whether this specific biochemical behaviour plays a causative role in the observed phenotype. In summary, dual inhibition of TORC1/2 and MEK has potential for effective antitumor activity in CRCs with dysregulation of both signaling cascades. A better understanding of the molecular mechanisms responsible for the enhanced efficacy of this therapeutic combination will help defining the best biomarkers that need to be assessed in phase I combination trials. 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 653. doi:10.1158/1538-7445.AM2011-653