Oral Presentation 37th Lorne Cancer Conference 2025

Targeting androgen receptor to prevent cell state plasticity and chemotherapy resistance in triple-negative breast cancer (113644)

Heloisa H Milioli 1 2 3 , Beatriz P San Juan 1 , Soroor Hediyeh-zadeh 4 , Vanina Rodriguez 1 , Carley A Purcell 1 2 , Shabarni Gupta 1 2 3 , Cerys McCool 1 2 , Felix V Kohane 1 2 5 , Sofia RE Mason 1 2 3 , Abigail Bunkum 1 , Laura Rangel-Sanchez 1 6 , Anie Kurumlian 1 , Lesley Castillo 1 , Narjis Fatima 1 , Dharmesh D Bhuva 7 , Elgene Lim 1 2 3 , Melissa J Davis 4 8 , Leonard D Goldstein 1 2 3 , Neha Aggarwal 9 , Natalie Walsh 10 , Kate Saw 1 , Mariz Selga 10 , Rasha Cosman 1 2 3 , Theresa E Hickey 11 , Jia Liu 1 2 3 12 , John G Lock 5 , Rachel Dear 1 2 3 , Christine L Chaffer 1 2 3
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. University of New South Wales, Sydney, NSW, Australia
  3. St Vincent’s Clinical School Faculty of Medicine, Sydney, NSW, Australia
  4. Walter and Eliza Hall Institute of Medical Research, , Parkville, VIC, Australia
  5. Department of Pathology, UNSW Medicine, Sydney, NSW, Australia
  6. School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
  7. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  8. School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia
  9. The Canberra Hospital, Canberra, ACT, Australia
  10. The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
  11. Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide, Adelaide, NSW, SA
  12. Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive breast cancer subtype that lacks targeted hormonal and HER2-directed treatments. Although conventional chemotherapies show initial efficacy, metastasis and resistance universally arise in advanced-stage TNBC. Addressing the aggressive nature of TNBC is critical for improving survival outcomes for these patients. In this study, we sought to identify and validate a clinical biomarker and matched targeted therapy to prevent and treat chemotherapy-resistant TNBC. We isolated CCSs and non-CSC populations from breast cancer cell lines, mapped them to clinical patient samples and performed a ‘multiome’ approach to validate a driver of aggressive TNBC. Our findings revealed androgen receptor (AR) as a clinical biomarker linked to poor therapy response and adverse outcomes in TNBC patients. We further demonstrated that AR sustains the aggressive CSC phenotype and drives resistance to chemotherapy. Using extensive pre-clinical models, we showed that the dual CYP17 lyase/AR inhibitor seviteronel effectively sensitized TNBC to chemotherapy, through concurrent inhibition of AR and MYC signalling, coupled with the suppression of the PI3K/AKT/mTOR pathway. In contrast, abiraterone and enzalutamide, inadvertently activated these oncogenic signalling, reducing their effectiveness in TNBC. Building on our preclinical results, we conducted a Phase 1 clinical trial (NCT04947189) demonstrating the safety of seviteronel in combination with taxane-based chemotherapies in patients with metastatic breast cancer. Early evidence of clinical efficacy led to a Phase 2 expansion study currently underway. Our work represents a significant step toward addressing the clinical challenge of targeting aggressive TNBC and developing effective treatment options to abrogate resistance across a range of AR-positive cancer types.