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.