Estrogen Receptor (ER) signalling, upregulation of the cyclin/CDK pathway, and suppression of p53 form a critical axis controlling proliferation of ER positive breast cancer. In this setting, mutation of p53 is relatively rare and suppression of p53 function can be achieved via regulators MDM2 and MDMX. Activation of p53 by inhibition of MDM2 is a promising therapeutic target in p53 wildtype tumours and several drugs are currently in clinical trials. We hypothesised that the MDM2 inhibitor NVP-CGM097 (Novartis, Phase I) will synergise with treatments that target ER signalling and cyclin/CDK activity by disrupting the complex feedback mechanisms that promote cell cycle entry and growth in ER positive breast cancer. We investigated the activity of CGM097 in vitro and in vivo in combination with selective ER degraders (SERDs). We show that CGM097 is an effective monotherapy in vitro and that response depends upon p53 status. CGM097 synergises with SERDs to inhibit proliferation, causing downregulation of cell cycle associated transcripts, cell cycle arrest, senescence and apoptosis. In vivo, CGM097 is as effective as endocrine therapy in an endocrine sensitive breast cancer PDX and resensitises an endocrine resistant PDX to endocrine therapy. CDK4/6 inhibitors are poised to become the new standard of care for advanced ER positive breast cancer. Using in vitro models of treatment naïve and CDK4/6-inhibitor resistant breast cancer, we show that CGM097 synergises with CDK4/6 inhibitors to strongly reduce proliferation and proliferation-associated transcripts in the treatment naïve setting; and causes cell cycle arrest and an accumulation of markers of senescence in models of Palbociclib resistance. In conclusion, MDM2 inhibition suppresses several proliferative pathways, including those deregulated in the acquisition of treatment resistance, and offers a rational therapeutic option for treating advanced and treatment resistant ER positive breast cancer.
17 Mar 2019 - 20 Mar 2019