Positioning A Selective, Bi-Steric Inhibitor Of Mtorc1 As A Combination Partner In Ras-Driven Cancers

The RAS and PI3K/mTOR signaling pathways function downstream of receptor tyrosine kinases (RTK), and are hyperactivated in a wide range of human cancers. Several points of cross-talk and intersecting feedback mechanisms have also been described, in which inhibition of one pathway node leads to activation of the parallel signaling pathway, thereby decreasing the effectiveness of single-pathway targeted therapies. Concomitant inhibition of both pathways is clearly effective in RAS-driven cancers as demonstrated via genetic means and by the combination of pharmacologic inhibitors of MEK and PI3 kinase in a variety of preclinical models (Engelman 2008, Collisson 2012, Eser 2013) However, the clinical translation of this combination has been largely unsuccessful, primarily due to development of dose-limiting toxicities that prohibit the achievement of optimal therapeutic drug concentrations. Recent advances in the treatment paradigm for RAS mutant non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) include several first-in-class covalent inhibitors of KRASG12C (e.g., AMG510, MRTX849) which have demonstrated a favorable safety profile along with early promising anti-tumor activity in patients with advanced cancers harboring a KRASG12C mutation. Drug-anchored CRISPR screens and combination experiments have identified mTOR signaling as a key mediator that limits therapeutic response to KRASG12C inhibition (Molina-Arcas 2019, Hallin 2019). We have developed a novel class of selective mTORC1 inhibitors, termed ‘bi-steric9, that covalently links rapamycin analogs with a mTOR kinase active-site inhibitor, and interacts with both the ATP- and FKBP12/FRB-binding sites of mTORC1. These compounds exhibit potent and selective (>10-fold) inhibition of mTORC1 over mTORC2, durably suppress S6K and 4EBP1 phosphorylation, and induce growth suppression and apoptosis in multiple cancer cell lines. In preclinical tests, these mTORC-1 selective inhibitors do not induce hyperglycemia and are predicted to have reduced mTORC2-mediated toxicities. We tested the combinatorial activity of these mTOR inhibitors and covalent KRASG12C inhibitors in preclinical models of two KRASG12C mutant tumor types predicted to have limited sensitivity to KRASG12C inhibitor monotherapy: a) STK11 deficient NSCLC wherein activation of mTORC1 signaling is also an oncogenic driver (~20% co-occurrence in KRAS-mutant NSCLC, Scheffler 2018) and b) colorectal cancer wherein RTK activation is thought to co-activate PI3 kinase signaling (Ebi, 2011). In each case, we showed combinatorial activity manifest as decreased tumor cell viability in vitro and tumor regressions in vivo. In contrast, single agents exhibited cytostatic effects in vitro and modest effects on tumor growth in vivo. Our data demonstrate that the combination of KRASG12C and bi-steric mTORC1 selective inhibitors elicits marked anti-tumor activity at well tolerated doses in vivo in models of cancer patient populations with current unmet medical need. The mechanistic bases for these combinatorial effects are currently under investigation. Our preclinical results reinforce the importance of mTORC1 as a concurrent target in genetically defined RAS-mutant cancers, and showcase the therapeutic potential of a novel and selective bi-steric mTORC1 inhibitor, currently in IND-enabling studies. Citation Format: Yu Chi Yang, Christopher Schulze, Jingjing Jiang, Denise F. Reyes, Tiffany Choy, Tram Nguyen, Zhican Wang, Dong Lee, Robert J. Nichols, Zhengping Wang, Jacqueline A. Smith, Steve M. Kelsey, Mallika Singh. Positioning a selective, bi-steric inhibitor of mTORC1 as a combination partner in RAS-driven cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-113.