Poster Presentation 35th Lorne Cancer Conference 2023

Selective androgen receptor modulators in combination with CDK4/6 inhibitors demonstrate anti-cancer activity in preclinical treatment resistant ER+AR+ breast cancer models (#146)

Allegra Freelander 1 2 , Geraldine Laven-Law 3 , Leila Eshraghi 1 2 , Nimmy Geetha 1 , Peta Somerville 1 , Marie Pickering 3 , Sarah Alexandrou 1 2 , Liz Caldon 1 2 , Wayne Tilley 3 , Theresa Hickey 3 , Elgene Lim 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, Faculty of Medicine, UNSW , Sydney, NSW, Australia
  3. Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia

Background: The Androgen Receptor is expressed in up to 90% of all ER+ breast cancers and has been associated with better patient outcome. While used as an anticancer therapy historically, Androgens are limited in its use due to their virilising effects. Non-steroidal, tissue Selective AR  Modulators (SARMs) represent an attractive alternative, offering a targeted approach to AR activation without the virilising effects. Recently, there has been compelling pre-clinical data establishing that the AR is a tumour suppressor, where treatment with SARMs acts to suppress ER-driven tumour growth, in endocrine-sensitive and -resistant ER+ breast cancer. Here, we evaluate the use of SARMs in the context of metastatic, CDK4/6 inhibitor (CDK4/6i) resistant breast cancer.

Methods: SARM/DHT and CDK4/6i were evaluated in vitro by colony forming assays in CDK4/6i resistant and combination endocrine and CDK4/6i resistant cell lines, and in vivo in an endocrine and CDK4/6i resistant ER+ patient derived xenograft (PDX) and cell line xenograft models. IHC, RNA and ChIP sequencing were subsequently performed on the harvested tumours from the 5 day treated cohort.

Results: Combination AR agonism and CDK4/6i effectively inhibited the growth of CDK4/6i-resistant preclinical models in vitro and in vivo. Gene set enrichment analysis and ChIP-seq showed upregulation of an AR gene signature associated with better prognosis following treatment with SARM. AR signalling was increased following treatment with CDK4/6i, indicating an interaction of the two signalling pathways.

Conclusion: Our data indicates that combination SARM and CDK4/6i represents a promising therapeutic strategy for treatment refractory ER+AR+ breast cancers.