Abstract 4744: State-gating cancer to prevent chemotherapy-resistance

Abstract New approaches are urgently required to treat advanced-stage cancers that are therapy resistant and incurable. Furthermore, salvage treatment protocols rely on cytotoxic chemotherapies that actively induce cancer cells to transition into therapy-resistant states via non-genetic mechanisms. We show in large clinical cohorts of triple-negative breast cancer (TNBC) that chemotherapy-induced cell state changes are mediated by androgen receptor (AR) signaling and are associated with poor patient outcome. AR inhibition blocks canonical and non-canonical AR signaling to lock cancer cells in therapy-sensitive states, and synergizes with a broad spectrum of cytotoxic chemotherapies to improve survival in pre clinical TNBC models. Seviteronel, a dual CYP17 lyase and AR inhibitor, faithfully mimics genetic AR ablation and is the most effective AR inhibitor in combination with chemotherapy. A Phase 1 clinical trial (NCT04947189) confirmed the safety of combining seviteronel with taxane chemotherapies in metastatic breast cancer. Early signs of clinical efficacy in patients with advanced disease led to a Phase 2 expansion study for AR-positive TNBC. These data provide proof-of-concept for AR inhibition as a ‘state-gating’ strategy to lock cancer cells in therapy-sensitive states and prevent the emergence of chemotherapy-resistance in TNBC. This paradigm may be widely applicable to other cancers. Citation Format: Christine Louise Chaffer, Heloisa H. Milioli, Beatriz P. San Juan, Rachel F. Dear, Jia (Jenny) Liu. State-gating cancer to prevent chemotherapy-resistance [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 4744.