Abstract 4451: Long-term resistance to PI3K/mTOR inhibition requires increased expression of c-myc and YAP.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC We have shown that extracellular matrix (ECM) contact contributes to PI3K/mTOR inhibitor resistance, where drug treatment leads to cytostasis but not cell death in ECM-attached cells. These cells do undergo proliferation arrest and this may reflect the situation in vivo, where PI3K/mTOR inhibitor treatment initially leads to growth arrest of the tumor cells. However this is often followed by re-initiation of proliferation, leading to relapse. In this study we have investigated the underlying molecular mechanisms that mediate long-term resistance to PI3K/mTOR inhibitors by selecting for cancer cells that proliferate after chronic inhibitor exposure in 3D cell cultures. To assess the mechanism of resistance, we performed reverse phase protein and RNA-seq arrays to identify signaling pathways that were altered in proliferating drug resistant cells. The protein arrays revealed up-regulated levels of c-myc and the Hippo pathway effector, YAP, in the resistant cells, and introduction of exogenous c-myc and YAP into drug sensitive cells rendered them resistant. While expression of c-myc alone induced partial resistance, YAP was also required, as knock-down of endogenous YAP resulted in loss of resistance. These data suggest that c-myc alone is not sufficient for generating resistance to PI3K/mTOR inhibitors, but an additional driver is required. Since the Hippo pathway is another major growth-promoting pathway (in addition to mTOR), it is conceivable that YAP compensates for the loss of mTOR signaling, contributing to resistance. Our current efforts are aimed at elucidating the mechanism by which YAP and c-myc mediate drug resistance to PI3K/mTOR inhibitors. Preliminary data suggests that c-myc-dependent glutamine metabolism contributes to drug resistance, as inhibition of glutaminase prevents resistance. Citation Format: Taru E. Muranen, Jonathan Coloff, Laura Selfors, Amy Bui, Gordon B. Mills, Joan S. Brugge. Long-term resistance to PI3K/mTOR inhibition requires increased expression of c-myc and YAP. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4451. doi:10.1158/1538-7445.AM2013-4451