Abstract B048: Tolinapant sensitizes PTEN-deficient prostate cancer to radiotherapy by targeting anti-apoptotic pathways

Abstract Introduction High-risk prostate cancer (PCa) with loss of the tumour suppressor gene phosphatase and tensin homolog (PTEN) remains clinically challenging, often progressing despite radiotherapy (RT) and androgen receptor (AR) pathway inhibition. PTEN loss contributes to immune-mediated radioresistance, in part through pro-inflammatory cytokine tumour necrosis alpha (TNF-α)–induced upregulation of cellular inhibitor of apoptosis proteins (cIAP1/2 and XIAP), promoting survival and treatment resistance. This study investigated the efficacy of inhibition of IAPs using tolinapant as a radiosensitiser in PTEN-deficient PCa models and explored its potential synergy with AR inhibition using enzalutamide. We hypothesised that pharmacological inhibition of IAPs would overcome RT resistance in PTEN-deficient PCa and augment apoptotic signalling. Methods Quantitative cell-based assays, immunofluorescence and Western blotting were used to evaluate tolinapant-mediated inhibition of IAP related proteins in PTEN-deficient and wildtype (WT) PCa cell lines both alone and in combination with radiation and enzalutamide, and the impact of these treatments on cell viability, survival and apoptosis. Xenograft mouse models of PTEN-deficient PCa were employed to assess tolinapant’s radio-sensitizing effects in vivo both as a single agent and in combination with RT, whilst ex vivo mechanistic studies focused on apoptotic signalling pathways. Results Tolinapant significantly enhanced the radiosensitivity of PTEN-deficient PCa cells, reducing cell viability and colony formation, with minimal impact in PTEN-WT cells. In xenograft models, tolinapant significantly delayed tumour progression, reduced proliferation (Ki67) expression and increased apoptosis (cleaved caspase-3) compared to RT alone. Ex vivo analyses confirmed on-target IAP suppression and activation of apoptosis pathway. Preliminary in vitro data suggest that adding enzalutamide further enhances radiosensitivity in PCa models, warranting further evaluation. Conclusion Our findings support tolinapant as a radiosensitiser in PTEN-deficient PCa, offering a promising therapeutic pathway for patients with high-risk or castration-resistant disease. By targeting anti-apoptotic signalling, tolinapant may enhance standard-of-care RT and delay disease progression. Ongoing studies aim to define optimal combinatorial strategies for clinical translation. Citation Format: Letitia Mohamed-Smith, Dimitra Kalamida, Suneil Jain, David J. Waugh, Melissa J. LaBonte-Wilson. Tolinapant sensitizes PTEN-deficient prostate cancer to radiotherapy by targeting anti-apoptotic pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B048.