Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care vascular endothelial growth factor tyrosine kinase inhibitors (VEGFR-TKIs).
HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then co-treated with both HC-5404 and VEGFR-TKIs in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.
VEGFR-TKIs including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKIs across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ~20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, 9/18 models responded with ≥50% tumor regression from baseline in the combination group.
By disrupting an adaptive stress response evoked by VEGFR-TKIs, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard of care therapies in RCC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Sep 21 [Epub ahead of print]
Michael E Stokes, Veronica Calvo, Sho Fujisawa, Crissy Dudgeon, Sharon Huang, Nupur Ballal, Leyi Shen, Jennifer Gasparek, Matthew Betzenhauser, Simon J Taylor, Kirk A Staschke, Alan C Rigby, Mark J Mulvihill, Nandita Bose, Eric S Lightcap, David Surguladze
HiberCell, Inc., New York City, United States., HiberCell, Inc., New York, United States., HiberCell, Inc., New York, NY, United States., HiberCell, Inc., United States., Massachusetts Institute of Technology, Cambridge, United States., Curia Global, United States., Pharmaron (United Kingdom), Hoddesdon, United Kingdom., Indiana University School of Medicine, Indianapolis, IN, United States., HiberCell, Inc., New York City, NY, United States., HiberCell, United States., HiberCell, Inc., Boston, MA, United States.