Overcoming mTOR Resistance Mutations with a New Generation mTOR Inhibitor

Precision medicines exert selective pressure on tumor cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next generation therapies to treat the evolving cancer. The PIK3CA/AKT/mTOR pathway is one of the most commonly activated pathways in human cancers1, which has led to the development of small molecule inhibitors that target various nodes in the pathway. Among these agents, first generation mTOR inhibitors (rapalogs) have caused responses in so-called “N-of-1” cases and second generation mTOR kinase inhibitors (TORKi) are currently in clinical trials2–4. We sought to delineate the likely resistance mechanisms to existing mTOR inhibitors as a guide for next generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active site mutation interfering with drug binding. Indeed, the identical drug resistant mutations have been also identified in drug-naïve patients4, suggesting that tumors with activating mTOR mutations will be intrinsically resistant to second generation mTOR inhibitors. Here, we report the development of a new class of mTOR inhibitors which overcomes resistance to existing first and second generation inhibitors. The third generation mTOR inhibitor exploits the unique juxtaposition of two drug binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.