Abstract 4586: p97/VCP inhibition with CB-5339 induces REDD1-dependent antitumor activity in renal cell carcinoma

Abstract Renal cell carcinoma (RCC) is the tenth most common cancer in the United States and disproportionately affects Hispanic and Native American populations, who experience higher incidence and mortality. Although current therapies targeting tyrosine kinases and immune checkpoints have extended survival, most patients ultimately develop resistance. This emphasizes the need for novel treatment strategies that disrupt essential survival pathways. The AAA+ ATPase p97/valosin-containing protein (VCP) is a central regulator of protein quality control that extracts misfolded or unfolded proteins from the endoplasmic reticulum (ER) for degradation, thereby preventing proteotoxic stress. We demonstrated that genetic knockdown of p97 significantly reduced RCC cell viability, supporting p97 as an essential survival factor and a promising therapeutic target. Consistent with this, the orally bioavailable, clinically relevant p97 inhibitor CB-5339 potently induced ER stress and apoptosis across human RCC cell lines and in Hispanic and Native American patient-derived xenograft (PDX) models. Transcriptomic profiling identified REDD1 as the most strongly upregulated gene following CB-5339 treatment. CRISPR-mediated knockout studies showed that REDD1 was required for maximal induction of ER stress and apoptosis, indicating that CB-5339 triggers a REDD1-dependent stress response. Because REDD1 is a negative regulator of mTORC1, we further assessed downstream effects on nutrient-sensing pathways. CB-5339 treatment inhibited mTORC1 activity and activated autophagy, as confirmed by autophagic flux assays using the lysosomal inhibitor bafilomycin-A1. Therefore, we hypothesized that combining p97 inhibition with autophagy blockade would enhance cytotoxicity by preventing the compensatory autophagic response. Consistent with this, co-treatment with CB-5339 and the lysosomal autophagy inhibitor ROC-325 produced strong synergy, significantly increasing apoptosis and reducing viability compared with either agent alone. In RCC xenograft models, the combination achieved marked tumor suppression, robust induction of apoptotic signaling, and excellent tolerability. Together, these results identify p97 as a novel therapeutic vulnerability in RCC and demonstrate that CB-5339’s anticancer effects are driven by REDD1-mediated ER stress and cell death. The synergistic efficacy of CB-5339 and ROC-325 highlights the therapeutic potential of combining proteostasis disruption with autophagy inhibition. Moreover, the use of multiple RCC PDX models enhances the translational relevance of this approach and provides a strong rationale for clinical investigation of p97 inhibition alone and in combination with autophagy-targeting agents in RCC. Citation Format: Sruthi Sureshkumar, Claudia M. Espitia, Maria Janina Carrera Espinoza, Madison Gamble, Natalie Hakim, Kevin Kelly, Jennifer S. Carew, Steffan T. Nawrocki. p97/VCP inhibition with CB-5339 induces REDD1-dependent antitumor activity in renal cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4586.