Mechanisms of Resistance to mTOR Targeted Therapies

The broad objective of this proposal is to investigate the intrinsic mechanisms of tumor cell resistance to newly developed mTOR inhibitors such that their future use may be optimized in the clinic. We have identified an alternate mechanism of mRNA translation initiation that is activated upon mTOR inhibitor exposure allowing tumor cell survival in the face of global inhibition of protein synthesis. These experiments will delineate the molecular mechanisms promoting activation of this salvage pathway and will pre-clinically evaluate the repurposing of an FDA-approved drug as a small molecule inhibitor targeting this pathway for synergistic antitumor effects in combination with mTOR inhibitors. We will utilize a combination of genetic and biochemical approaches to address the mechanisms by which the salvage protein synthesis pathway is activated in TOR inhibitor resistant brain and breast cancers. We will utilize mouse models of these diseases to evaluate the efficacy of these inhibitors.