Abstract 2662: Bi-steric mTORC1 inhibitor RMC-6272 synergizes with immune checkpoint inhibitors to induce sustained regression of MYC-driven hepatocellular carcinoma
Authors: Mahauad-Fernandez Wadie D. , Yang Yu C. , Lai Ian , Park Jangho , Yao Lilian , Evans James W. , Smith Jacqueline A. , Singh Mallika , Felsher Dean W. 
Published: June 2022

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths in the world. Current treatments for HCC have limited efficacy. First-line HCC therapy atezolizumab with bevacizumab increased patient 6-month PFS from 37% to 55% relative to sorafenib, a multi-kinase inhibitor currently serving as a standard-of-care treatment. Although immunotherapies provide survival benefits, reported patient response and disease control rates were 27% and 74%, respectively, highlighting the need for novel therapeutic agents that can re-establish responsiveness to immunotherapies and enhance their therapeutic effects.
Revolution Medicines has developed a class of selective mTORC1 inhibitors, termed ‘bi-steric’, which comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. RMC-6272 is a representative bi-steric inhibitor that exhibits potent and selective (&gt;30-fold) inhibition of mTORC1 over mTORC2. Several lines of evidence suggest that inhibition of the mTORC1 pathway may result in synthetic lethality of MYC-driven HCC. Thus, we hypothesized that MYC-driven HCC tumors are sensitive to mTORC1 inhibition and p-4EBP1 suppression. A single dose of RMC-6272 induced HCC regression in 80% of the Lap-tTA/Tet-O-MYC mouse model of MYC-driven HCC, whereas sorafenib did not cause tumor regression. Mechanistically, RMC-6272 inhibited the phosphorylation of mTORC1 downstream substrates S6k and 4EBP1 and depleted MYC protein levels. Given that the MYC oncogene enables immune evasion in HCC, we hypothesized that by reducing MYC, RMC-6272 can re-establish anti-tumor immune surveillance and responsiveness to α-PD-1 immunotherapy. Indeed, RMC-6272 induced tumor recruitment of dendritic cells, T cells, B cells, and natural killer (NK) cells, producing similar anti-tumor immunity as observed upon MYC genetic inactivation. Moreover, combining RMC-6272 with α-PD-1 resulted in deeper tumor regression and a more durable response as compared to either RMC-6272 or α-PD-1 alone in the MYC-driven HCC mouse model. By immunohistochemical staining and analysis, RMC-6272 in combination with α-PD-1, but not either agent alone, promoted tumor recruitment of CD4+ T cells and NK cells, immune cell degranulation, and the release of perforins and granzymes in MYC-driven HCC tumors.
Our results show that the bi-steric mTORC1 inhibitor RMC-6272 synergizes with α-PD-1 to induce immune activation and the release of perforins and granzymes, resulting in sustained tumor regression in a MYC-driven HCC mouse model. The bi-steric mTORC1 inhibitor RMC-5552 is the first clinical candidate of this class and clinical testing is ongoing (NCT04774952). These preclinical data highlight a prospective anti-cancer therapeutic opportunity for mTORC1 selective inhibitors in combination with immune checkpoint inhibitors in MYC-driven cancers.
Citation Format: Wadie D. Mahauad-Fernandez, Yu C. Yang, Ian Lai, Jangho Park, Lilian Yao, James W. Evans, Jacqueline A. Smith, Mallika Singh, Dean W. Felsher. Bi-steric mTORC1 inhibitor RMC-6272 synergizes with immune checkpoint inhibitors to induce sustained regression of MYC-driven hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2662.