Abstract 4010: Inhibition of PERK by HC-5404 sensitizes clear cell renal cell carcinoma tumor models to anti-angiogenic tyrosine kinase inhibitors

Abstract Anti-angiogenic agents form the backbone of standard of care for advanced clear cell renal cell carcinoma (ccRCC), but their clinical impact is limited by primary and secondary resistance mechanisms that remain a critical problem. Furthermore, the approvals for VEGFR-targeting receptor tyrosine kinase inhibitors (VEGFR-TKIs), cabozantinib in second-line, and tivozanib in third-line RCC patients were based on modest objective response rates and median progression-free survival. There is an urgent need for novel mechanisms that target adaptive tumor responses that drive resistance to these agents, as well as combination drug partners that improve outcomes for patients. As part of their mechanism, VEGFR-TKIs induce oxygen- and nutrient-deprivation that drives ER stress. Tumors can evade deleterious ER stress by activating PERK branch of the integrated stress response, which arrests global translation and restores homeostasis. We hypothesized that inhibiting PERK would enhance the anti-tumor activity of VEGFR-TKIs in vivo and tested this using HC-5404, a potent and selective PERK inhibitor currently in Ph1 clinical testing (NCT04834778). Here, we present preclinical evidence that supports combining HC-5404 with VEGFR-TKIs in ccRCC. We demonstrate that axitinib, cabozantinib, lenvatinib, and sunitinib all activate PERK in 786-O ccRCC xenografts in a dose-responsive manner. The addition of HC-5404 significantly enhanced the tumor growth inhibition (TGI) of VEGFR-TKIs across multiple ccRCC tumor models, resulting in tumor stasis or regression in combination groups. Expression profiling and IHC analysis of tumor sections revealed that HC-5404 enhanced the anti-angiogenic effects of axitinib and lenvatinib in 786-O tumors, highlighting the protective role of PERK in response to anti-angiogenics. To evaluate whether the combination treatments could benefit a diverse patient population, sensitivity to HC-5404 and axitinib was evaluated across a panel of patient-derived xenograft (PDX) models. This experiment confirmed widespread responsiveness to the combination treatment that in some cases achieved >50% tumor regression. As tumor progression on VEGFR-TKIs limits the success of these agents in the clinic, we evaluated the effect of adding HC-5404 to tumors that have previously progressed on axitinib. In this study, 786-O xenografts were treated with axitinib for 2-weeks and non-responders were rerandomized into groups of either single agent or combination of HC-5404 and axitinib. The combination treatment significantly improved TGI relative to either monotherapy, resulting in tumor regression of ~20%. Taken together, these findings highlight that by disrupting an adaptive stress response evoked by VEGFR-TKIs, HC-5404 presents a clinical opportunity to enhance the anti-tumor effects of well-established standard of care therapies in ccRCC. Citation Format: Michael E. Stokes, Veronica Calvo, Crissy Dudgeon, Sho Fujisawa, Sharon Huang, Leyi Shen, Nupur Ballal, Joe McGinley, David Liu, Mark J. Mulvihill, Alan C. Rigby, Nandita Bose, Eric S. Lightcap, David Surguladze. Inhibition of PERK by HC-5404 sensitizes clear cell renal cell carcinoma tumor models to anti-angiogenic tyrosine kinase inhibitors. [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 4010.