Abstract B024: KO-2806, a next-generation farnesyltransferase inhibitor, potentiates the antitumor activity of cabozantinib in clear cell renal cell carcinoma models

Abstract

Abstract Conventional treatments for advanced clear cell renal cell carcinoma (ccRCC) include tyrosine kinase inhibitors (TKI) that target angiogenesis, a critical element for ccRCC tumor growth and survival. Cabozantinib, a TKI that inhibits VEGFR, AXL, and MET, is an approved therapy in advanced RCC. However, cabozantinib has limited therapeutic benefit; for example, patients with prior VEGFR TKI therapy had an overall response rate of 21% and median progression-free survival of 7.4 months. Thus, there is an urgent need to identify combination drug partners that can improve the depth and/or durability of clinical responses to cabozantinib.   Here, we present preclinical evidence that supports combining the farnesyltransferase inhibitor (FTI), KO-2806, with cabozantinib in ccRCC. KO-2806 is a next-generation farnesyltransferase inhibitor with increased potency and improved pharmacokinetic properties relative to earlier FTI drug candidates and is poised to enter a first-in-human clinical trial. We demonstrate that addition of KO-2806 enhanced tumor growth inhibition of cabozantinib in multiple ccRCC cell line- and patient-derived xenograft models, resulting in either tumor stasis or regression. Immunohistochemical analysis of angiogenic markers in 786-O tumors revealed that, consistent with its mechanism of action, cabozantinib significantly reduced angiogenesis, an effect that was deepened by KO-2806. In support of this, cell viability experiments performed in primary human endothelial cells showed that the combination of KO-2806 and cabozantinib was more effective in reducing cell viability than cabozantinib alone.   In addition, we investigated the mechanism underlying the improved response of tumors with the KO-2806-cabozantinib combination by analyzing the major growth signaling pathways in 786-O tumors. Cabozantinib alone reduced both MAPK and PI3K/AKT/mTOR signaling, but addition of KO-2806 resulted in enhanced inhibition of mTOR signaling and increased cell cycle arrest compared to either agent alone. We hypothesize that exposure to anti-angiogenic TKIs render ccRCC tumors more hypoxic, and thus more reliant on compensatory, oncogenic mechanisms like mTOR signaling that allow them to adapt to a nutrient- and oxygen-deprived environment. Mechanistically, KO-2806 potently inhibits the farnesylation, and hence the activity, of the farnesylation-dependent protein RHEB, a positive regulator of mTOR, suggesting that the improved anti-tumor efficacy of the combination may arise through RHEB inhibition in this model. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of the effects of the KO-2806-cabozantinib combination and strengthen the therapeutic rationale for the investigation of this approach in the treatment of patients with ccRCC. Citation Format: Jovylyn Gatchalian, Linda Kessler, Hetika Patel, Stacia Chan, Francis Burrows, Shivani Malik. KO-2806, a next-generation farnesyltransferase inhibitor, potentiates the antitumor activity of cabozantinib in clear cell renal cell carcinoma models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B024.