Resistance to standard-of care-therapies is a significant clinical challenge in estrogen receptor positive (ER+) breast cancer. Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapies (ET) is the current standard-of-care for advanced metastatic ER+ breast cancer; however, resistance to this combination is considered inevitable, leading to disease progression. The androgen receptor (AR) is expressed in up to 90% of all ER+ breast cancers, and has been associated a good prognosis. Compelling recent pre-clinical data demonstrates that selective androgen receptor AR modulators (SARMs) act to suppress ER-driven tumour growth of endocrine-sensitive and –resistant models of ER+ breast cancer. Furthermore, a recent clinical trial evaluating the efficacy of SARMs has shown clinical benefit in patients with ER+/AR+ metastatic breast cancer (NCT02463032). We hypothesise that SARMS, either alone or in combination with a CDK4/6i, would be an effective treatment for tumours that are sensitive and resistant to ET and CDK4/6i.
We report therapeutic efficacy of combination AR agonism + CDK4/6i in CDK4/6-naïve and –resistant pre-clinical models, including cell lines and patient derived xenograft (PDX) models. We demonstrate that combination SARM + CDK4/6i potently and durably inhibited in vitro and in vivo tumour growth. Additionally, we provide evidence that in vivo treatment with the CDK4/6i Palbociclib increased AR expression and signalling, highlighting an interaction of the two signalling pathways not previously described.
In conclusion, our data provides a pre-clinical rationale for combination SARM + CDK4/6i in CDK4/6i resistant ER+ breast cancer.