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The integrated stress response (ISR) is an adaptive signaling pathway that cells utilize to respond to a wide range of extrinsic and intrinsic stresses, which are important for tumorigenesis. Activation of ISR is suggested to play a dual role in cell fate decisions. While the ISR promotes survival, prolonged activation of ISR induces apoptosis. We are developing HC-7366, a first-in-class, first-in-human GCN2 activator, and are currently evaluating it in a phase 1 clinical trial in solid tumors (NCT05121948). In this study, we present the characterization of the antitumor effects of HC-7366 in solid tumors. In vivo efficacy studies using HC-7366 montherapy showed significant tumor growth inhibition (TGI%) in preclinical cancer models of colorectal (78-95%), head and neck (33% regression), sarcoma (80%) and prostate (65%). HC-7366 activated the ISR in tumors from treated mice as evidenced by induction of the ATF4 target genes ASNS and PSAT1. Additionally, HC-7366 induced the proapoptotic protein PUMA and reduced HIF1⍺ and HIF2⍺ levels. Furthermore, HC-7366 showed significant benefit in colorectal models when combined with DC101 (anti-VEGFR2 antibody), 5-fluorouracil (chemotherapy), alpelisib (PI3Kα inhibitor), or trametinib (MEK1/2 inhibitor). Using GCN2 CRISPR-knockout cells, we confirmed that the HC-7366 mediated reduction of cell growth and induction of ISR markers was dependent on GCN2. We performed multi-omics analyses to further understand the mechanism of action. Metabolomics analysis of tumors treated with HC-7366 revealed that HC-7366 altered several metabolites involved in amino acid metabolism, oxidative stress, the urea cycle, and pyrimidine biosynthesis. Additionally, proteomics analysis showed that HC-7366 significantly reduced proteins involved in oxidative phosphorylation. Analysis of the transcriptome in tumors from treated mice demonstrated that HC-7366 reduced the activity of HIF and E2F1-driven transcription, including expression of metaphase-anaphase transition genes, consistent with decreased Ki67 staining in tumors. ATF4 and JUN transcriptional activity was enhanced with HC-7366 treatment consistent with activation of ISR. Collectively, our in vitro and in vivo results demonstrate that HC-7366 is a potent GCN2 activator with strong antitumor activity across multiple solid tumor models as a monotherapy or in combination with standard of care agents. Citation Format: Feven Tameire, Paulina Wojnarowicz, Crissy Dudgeon, Sho Fujisawa, Sharon Huang, Owen B. Reilly, Nicholas Collette, Jeremy Drees, Kathryn Bieging-Rolett, Takashi O. Kangas, Weiyu Zhang, Maria Fumagalli, Iman Dewji, Yunfang Li, Anissa SH Chan, Xiaohong Qiu, Ben Harrison, Ashley LaCayo, Ricardo A. Cordova, Kirk A. Staschke, Alan C. Rigby, Savithri Ramurthy, Eric S. Lightcap, David Surguladze, Nandita Bose. Activation of GCN2 by HC-7366 results in significant antitumor efficacy as monotherapy and in combination with multiple standard of care agents in various solid cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6231. |
