Abstract 5593: The multi-kinase inhibitor tinengotinib as a novel therapy for advanced prostate cancer
Authors: Brandon Hernandez, Jason Somarelli, Andrew Armstrong, Anaya Dutta, Bilal Ashraf, Xiaoyan Qiang, Yichang Zeng, Peng Peng, Jean Fan
Journal: Cancer Research (2025)

Abstract Purpose: Metastatic castration-resistant prostate cancer (mCRPC) is responsible for nearly 30, 000 deaths each year in the US. While androgen receptor pathway inhibitors (ARPIs) significantly prolong the lives of men with mCRPC, the evolution of resistance to these agents is nearly universal. Among the mechanisms of resistance to ARPIs, studies have pinpointed activation of JAK/STAT and fibroblast growth factor receptor (FGFR) signaling as key mediators of ARPI resistance by mediating lineage plasticity and loss of AR dependence. To target these multiple resistance mechanisms, we interrogated the potential of tinengotinib, a spectrum-selective multi-kinase inhibitor for the treatment of ARPI-resistant mCRPC that targets Aurora Kinase A/B, JAK1/2, FGFRs and VEGFRs. Our study aims to characterize efficacy and resistance mechanisms of tinengotnib in prostate cancer cell lines and to develop novel combinatorial treatment strategies for mCRPC. Methods: Baseline expression of Aurora A/B, STAT3, JAK1/2, VEGFR1/2/3, FGFR1/2/3, and CS1FR in a panel of prostate cancer cell lines (LNCaP, LNCaP95, LNCaP XER, 22RV1, PC3, and LASCPC-01) was assessed by qPCR and western blots. Single-agent and combination dose-response curves were performed with tinengotinib and standard-of-care agents using IncuCyte imaging and CellTiter Glo. Small molecule inhibition was used to assess the role of tinengotinib targets in driving cancer cell survival and growth. Results: Tinengotinib potently inhibited growth of all cell lines, including enzalutamide-sensitive and -resistant AR signaling-dependent models (LNCaP, LNCaP95, LNCaP-XER), double negative models (PC-3) and neuroendocrine-like (LASPC-01) lineages, with IC50s ranging from low nanomolar to ∼1 μM. Tinengotinib demonstrated additive effects with enzalutamide. Consistent expression of Aurora A and B, JAK2, and FGFR3 was observed across all cell lines while VEGFRs and FGFR1, 2, and 4 showed more variation in expression across lines. Interrogation of potential drivers will be presented. Conclusion: Preclinical evaluation of tinengotinib shows efficacy across a range of prostate cancer phenotypes and combined effectively with standard agents. Gene expression across this panel of cell lines pinpoints Aurora A and B, JAK2, and FGFR3 as potential mechanisms of action for tinengotinib in prostate cancer. Future studies are aimed at understanding its mechanisms of action and determining its potential as a combination therapy for mCRPC. Citation Format: Brandon Hernandez, Jason Somarelli, Andrew Armstrong, Anaya Dutta, Bilal Ashraf, Xiaoyan Qiang, Yichang Zeng, Peng Peng, Jean Fan. The multi-kinase inhibitor tinengotinib as a novel therapy for advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5593.