Abstract PR03: The Hippo pathway effector YAP1 contributes to escape from proliferation arrest under chronic PI3K/mTOR inhibition

Abstract

Abstract The PI3K/mTOR pathway is one of the most frequently mutated pathways in cancer. This pathway controls cell proliferation and cell survival, and represents an attractive target for cancer intervention. In animal tumor models, chronic treatment with PI3K/mTOR inhibitors initially induces tumor cytostasis. However, over time, tumor cells escape from drug-mediated proliferative suppression, resulting in relapse and tumor growth even in the presence of continued PI3K/mTOR inhibition. In this study we investigated the underlying molecular mechanisms that allow outgrowth of drug resistant tumor cells (“PI3K escapers”) after long-term treatment of tumor cell spheroids with PI3K/mTOR inhibitors. We identified several signaling pathways that were distinguishably altered in tumor cells that escaped proliferative suppression after chronic drug treatment compared to tumor cells acutely treated with inhibitor. Both MYC, which has been previously implicated in resistance to PI3K/mTOR inhibitors, and the Hippo pathway effector, YAP, were significantly upregulated in the “PI3K escapers” as well as multiple tumor cells lines that are resistant to PI3K/mTOR inhibition. Downregulation of either MYC or YAP abrogated the drug resistance. Although over-expression of MYC alone was sufficient to induce drug resistance, YAP was required for the MYC-induced resistant state, as knock-down of endogenous YAP resulted in loss of MYC-mediated resistance. Interestingly this resistance phenotype was associated with a KRAS or BRAF mutation, suggesting that MYC and YAP confer resistance in tumor cells in the context of ERK pathway activation. These data suggest that escape from proliferation suppression after chronic treatment with PI3K/mTOR in the context of activation of the KRAS pathway can be mediated by upregulation of MYC and YAP, which coordinately confer resistance. This abstract is also being presented as Poster B41. Citation Format: Taru Muranen, Laura M. Selfors, Carson C. Thoreen, Lisa L. Gallegos, Jonathan L. Coloff, Gordon B. Mills, Joan S. Brugge. The Hippo pathway effector YAP1 contributes to escape from proliferation arrest under chronic PI3K/mTOR inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr PR03.