Estrogen Receptor (ER) signalling, upregulation of the cyclin/CDK pathway, and suppression of p53 is a critical axis controlling proliferation of ER positive breast cancer. In this setting, mutation of p53 is relatively rare and suppression of p53 function is commonly achieved via regulators MDM2 and MDM4. MDM2 inhibition is a possible therapeutic intervention in p53 wildtype tumours, with several drugs currently in clinical trials. ER signalling activates the cyclin/CDK pathway and initiates proliferation; p53 blocks this pathway and promotes cell cycle arrest, senescence and apoptosis in response to DNA damage and other adverse events. In turn, ER partially supresses p53 by inhibition of p53 transcriptional activity.
We hypothesised that in the context of this complex feedback network, the MDM2 inhibitor NVP-CGM097 (Novartis) would synergise with treatments that target ER signalling, cyclin/CDK activity and the p53 axis.
Drug-mediated degradation of ER sensitises breast cancer cells to cytotoxic therapies by restoring p53 response. We investigated the activity of CGM097 in vitro and in vivo in combination with the ER degrader Fulvestrant. We show that CGM097 is an effective monotherapy in vitro and that response depends upon p53 status. CGM097 synergises with Fulvestrant to inhibit proliferation and upregulate a set of ER/p53 co-regulated transcripts. In vivo, CGM097 is as effective as Fulvestrant in an endocrine sensitive breast cancer PDX and resensitises an endocrine resistant PDX to Fulvestrant.
Deregulation of p53 increases Cdk4/6 via p21 suppression, and CDK4/6 inhibitors like Palbociclib are particularly effective cell cycle suppressors. Using in vitro models of treatment naïve and Palbociclib resistant breast cancer, we show that CGM097 synergises with Palbociclib to reduce proliferation 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.