Targeting mTORC1 with Bi-Steric Inhibitors: A Promising Therapeutic Strategy for RAS-Driven Cancers

The RAS and PI3K/mTOR signaling pathways are frequently hyperactivated in various human cancers, and their interplay complicates single-pathway targeted therapies. While combined inhibition of both pathways has shown promise in preclinical models, clinical application has been hindered by dose-limiting toxicities.

Advancements in treating RAS mutant non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) include covalent inhibitors of KRASG12C, which have shown promising safety and anti-tumor profiles. However, mTOR signaling has been identified as a key mediator that limits the therapeutic response to KRASG12C inhibition.

A novel class of 'bi-steric' selective mTORC1 inhibitors has been developed, which combines features of rapamycin analogs with mTOR kinase active-site inhibitors. These compounds potently inhibit mTORC1 over mTORC2, leading to durable suppression of S6K and 4EBP1 phosphorylation and inducing growth suppression and apoptosis in cancer cell lines. Notably, these mTORC1 selective inhibitors do not induce hyperglycemia and are expected to have reduced toxicities associated with mTORC2.

The combinatorial activity of these mTORC1 inhibitors with covalent KRASG12C inhibitors was tested in preclinical models of cancers with KRASG12C mutations and limited sensitivity to KRASG12C inhibitor monotherapy: STK11 deficient NSCLC and CRC. The combination therapy demonstrated increased anti-tumor activity in vitro and in vivo compared to single-agent treatments, which showed cytostatic effects and modest impacts on tumor growth.

The data supports the potential of combining KRASG12C inhibitors with bi-steric mTORC1 selective inhibitors to achieve significant anti-tumor effects at well-tolerated doses. The underlying mechanisms of these synergistic effects are under investigation. The results underscore the importance of targeting mTORC1 in RAS-mutant cancers and highlight the therapeutic potential of a new selective bi-steric mTORC1 inhibitor, which is currently in IND-enabling studies.