Abstract B010: Targeting SSTR1 to overcome resistance to androgen receptor signaling inhibition in prostate cancer

Abstract Background: Resistance to androgen receptor signaling inhibitors (ARSIs), such as abiraterone or enzalutamide (ENZ), is a major obstacle to improving outcomes for patients with prostate cancer. We previously identified SSTR1 to be transcriptionally downregulated in ARSI-resistant prostate cancer. SSTR1 encodes somatostatin receptor type 1, which mediates anti-proliferative, anti-invasive, and anti-angiogenic effects when binding to somatostatin or somatostatin analogues. Here, we studied the biology of SSTR1 in prostate cancer, focusing on its relationship with ARSI resistance and its potential as a therapeutic target. Methods: To examine the impact of ARSI on SSTR1 expression, we treated C42B and 22Rv1 cells and LTL484 and LTL331 patient-derived organoids (PDOs) with enzalutamide and determined SSTR1 expression after the treatment. To investigate the function of SSTR1, we generated stable knockdown (using CRISPR interference), CRISPR knockout, and stable lentiviral over-expression cell lines of C42B and 22Rv1. Using such cells, we assessed live cell number with and without enzalutamide treatment. To evaluate the therapeutic potential of targeting SSTR1, we tested CH275, a SSTR1-specific agonist, and pasireotide, the only FDA-approved SSTR1 agonist with a pan-SSTR activity. The effects of these SSTR1 agonists, alone or in combination with enzalutamide, were evaluated in C42B and 22Rv1 cells by live cell number, and in LTL484 and LTL331 PDOs by cell viability and apoptosis. Results: SSTR1 protein levels decreased after enzalutamide treatment in both cell lines and PDOs, consistent with decreased mRNA levels in tumor biopsies. CH275 and pasireotide decreased the live cell number of C42B and 22Rv1 cells. SSTR1 knockdown and knockout increased live cell number and attenuated the effect of CH275, whereas SSTR1 overexpression decreased live cancer cell number and enhanced the CH275 effect. Moreover, both SSTR1 agonists (CH275 and pasireotide) synergized with ARSIs (enzalutamide and apalutamide) in eliminating live cells. Similar trends were observed in LTL484 and LTL331 PDOs treated with pasireotide, enzalutamide, or their combination. SSTR1 knockdown and knockout attenuated the synergistic effects of combination treatment in both cell lines. Conclusions: ARSI treatment in CRPC models decreased SSTR1 expression. SSTR1 agonists enhanced the efficacy of ARSI in suppressing prostate cancer growth. These findings motivate the testing of SSTR1 agonists in preclinical models in vivo as a potential therapeutic approach to improve treatment response and outcomes for patients with prostate cancer. Citation Format: Shu Chen, Tianyi Liu, Jun Zhu, Haolong Li, David Quigley, Alan Ashworth, Rahul Aggarwal, Eric Small, Felix Feng, Xiaolin Zhu. Targeting SSTR1 to overcome resistance to androgen receptor signaling inhibition in prostate cancer 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 (2Suppl): Abstract nr B010.