Abstract LB015: Bi-steric mTORC1-selective inhibitors activate 4EBP1, suppress MYC, restore anti-tumor immunity, and cooperate with immune checkpoint inhibition to elicit tumor regression
Authors: Mahauad-Fernandez Wadie D. , Yang Yu Chi , Lai Ian , Park Jangho , Yao Lilian , Evans James W. , Atibalentja Danielle F. , Chen Xinyu , Zhao Zihui , Burnett G. Leslie , Lee Bianca J. , Dinglasan Nuntana , Shifrin Nataliya , Ahler Ethan , Quintana Elsa , Gill Adrian , Smith Jacqueline A. , Singh Mallika , Felsher Dean W. 
Published: April 2023

The mammalian target of rapamycin (mTOR) pathway is frequently involved in the pathogenesis of human tumorigenesis. mTOR forms two protein complexes: mTORC1 which responds to growth and stress factors resulting in the phosphorylation of 4EBP1 and S6K for their deactivation and activation, respectively; and mTORC2 which responds to growth factors resulting in pAKT activation. Through 4EBP1 and S6K, the mTORC1 complex regulates translation of oncogenes including MYC. The MYC oncogene is causally involved in the pathogenesis of many human cancers but remains as a challenging therapeutic target. Experimentally, inhibiting MYC results in tumor regression associated with immune reactivation. Several lines of evidence suggest that inhibition of the mTORC1 pathway may result in synthetic lethality of MYC-driven cancers. However, to date, existing mTOR pathway inhibitors such as everolimus or sapanisertib fail to sufficiently decrease MYC protein levels in vivo because of incomplete inhibition of p4EBP1 or toxicities that limit the activity, respectively. Revolution Medicines has developed third-generation bi-steric selective mTORC1 inhibitors with a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. RMC-5552, a representative of the bi-steric class of selective mTORC1 inhibitor, is currently in Phase 1 clinical trials (NCT04774952). Here, we show this new class of inhibitors suppresses both S6K and 4EBP1 phosphorylation and depletes MYC protein expression in vivo in an autochthonous conditional transgenic mouse model of MYC-driven HCC and across several human patient-derived xenograft models with MYC amplification. Furthermore, bi-steric mTORC1-selective inhibitors restore anti-tumor immune surveillance and synergize with α-PD-1 immune checkpoint therapy in the MYC-driven HCC mouse model. Overall, we provide proof-of-principle that selective mTORC1 pharmacological inhibition can effectively target MYC-driven cancers by reducing MYC levels, combine with immune checkpoint inhibition, re-establish anti-tumor immunity, and induce sustained tumor regression in the preclinical setting. These preclinical findings provide a rationale for clinical trials with selective mTORC1 inhibitors in patients with MYC-driven cancers and moreover, support clinical testing of combination with immune checkpoint inhibition.

Citation Format: Wadie D. Mahauad-Fernandez, Yu Chi Yang, Ian Lai, Jangho Park, Lilian Yao, James W. Evans, Danielle F. Atibalentja, Xinyu Chen, Zihui Zhao, G. Leslie Burnett, Bianca J. Lee, Nuntana Dinglasan, Nataliya Shifrin, Ethan Ahler, Elsa Quintana, Adrian Gill, Jacqueline A. Smith, Mallika Singh, Dean W. Felsher. Bi-steric mTORC1-selective inhibitors activate 4EBP1, suppress MYC, restore anti-tumor immunity, and cooperate with immune checkpoint inhibition to elicit tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB015.