Abstract 1002: A bi-steric mTORC1 inhibitor that selectively reactivates 4EBP1 and induces regression of MYC-driven hepatocellular carcinoma
Authors: Mahauad-Fernandez Wadie D. , Yang Yu C. , Lai Ian , Park Jangho , Evans James W. , Singh Mallika , Smith Jacqueline A. , Felsher Dean W. 
Published: July 2021

Hepatocellular carcinoma (HCC) accounts for ~90% of all liver cancers and is the third leading cause of cancer deaths in the world. HCC patients have a 5-year survival rate of 31%. Current treatments for HCC are scarce and have limited efficacy. These treatments include first-line therapy Sorafenib and second-line combination therapy nivolumab (anti-PD-1) with ipilimumab (anti-CTLA-4). The former therapy increased survival by less than 3 months and the latter increased survival from 37% to 68%. However, patient responses are variable and limited. Thus, there is a need to identify new therapies for HCC with sustained and efficacious 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-5552 is the first clinical candidate of this class and clinical testing is planned in 2021. Bi-steric mTORC1 inhibitors exhibit potent and selective (&gt;10-fold) inhibition of mTORC1 over mTORC2 and durably suppress p-S6K and p-4EBP1. Several lines of evidence suggest that inhibition of the mTORC1 pathway may result in synthetic lethality of MYC-driven HCC. Thus, we hypothesize that MYC-driven HCC tumors are sensitive to mTORC1 inhibition and p-4EBP1 suppression (4EBP1 reactivation). To test this hypothesis, we first evaluated the short-term in vivo effect of two representative bi-steric tool compounds, RM-001 and RM-006 (also known as RMC-6272) in the LAP-tTA/TRE-MYC mouse model of MYC-driven HCC. We compared their anti-tumor activity to first-line HCC therapy Sorafenib. Our results show that a single dose of RM-006 induced HCC regression in 80% of mice while RM-001 reduced HCC growth in 68% of mice and Sorafenib reduced tumor growth in 50% of mice. Mechanistically, we found that RM-006 potently and durably inhibits the phosphorylation of mTORC1 downstream effectors 4EBP1 and S6 (a direct substrate of the mTORC1 substrate S6K), and decreased protein expression levels of MYC. Our results show for the first time that inhibition of mTORC1 with concomitant suppression of p-4EBP1 drove regression in MYC-driven HCC tumors, and the significant anti-tumor activity of RM-006 may result from sustained reduction of MYC protein levels due to reduced protein translation upon 4EBP1 reactivation. Future directions will aim at defining whether RM-006 affects global MYC-regulated cell-intrinsic and host immune pathways. These preclinical data highlight a potential therapeutic opportunity for the investigational bi-steric mTORC1 inhibitor RMC-5552 in combination with immune checkpoint inhibitors to overcome MYC-mediated immune suppression. Under this potential therapeutic paradigm HCC patient survival may be extended via a dual mechanism that reduces MYC levels via 4EBP1 reactivation and that rescues anti-tumor immune surveillance.

Citation Format: Wadie D. Mahauad-Fernandez, Yu C. Yang, Ian Lai, Jangho Park, James W. Evans, Mallika Singh, Jacqueline A. Smith, Dean W. Felsher. A bi-steric mTORC1 inhibitor that selectively reactivates 4EBP1 and induces regression of MYC-driven hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1002.