Poster Presentation 32nd Lorne Cancer 2020

Synergistic targeting of estrogen-receptor positive breast cancers by MDM2 inhibition in combination with endocrine therapy or CDK4/6 inhibition (#331)

Neil Portman 1 2 , Heloisa Helena Milioli 1 2 , Sarah Alexandrou 1 2 , Rhiannon Coulson 1 3 , Aliza Yong 1 , Kristine J Fernandez 1 , Kee Ming Chia 1 , Davendra Segara 1 2 , Andrew Parker 1 2 , Alex Swarbrick 1 2 , Sue Haupt 3 , Ygal Haupt 3 , Elizabeth Caldon 1 2 , Elgene Lim 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia
  3. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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 the metastatic setting simultaneously inhibiting ER signalling and CDK4/6 activity is a very effective therapeutic strategy and has been adopted as standard of care. However, resistance still inevitably develops and there is currently no clear treatment strategy once this occurs.

 In the ER positive setting, mutation of p53 is relatively rare and suppression of p53 function can be achieved via the 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 MDM2 inhibition 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 MDM2 inhibition in vitro and in vivo in combination with selective ER degraders (SERDs) and CDK4/6 inhibition using models of endocrine resistance and CDK4/6 inhibitor resistance. We show that MDM2 inhibition is an effective monotherapy, causing downregulation of cell cycle associated transcripts, cell cycle arrest, senescence and apoptosis. We find that MDM2 inhibition is strongly synergistic with both endocrine therapy and CDK4/6 inhibition and that the mechanism of synergy is via profound inhibition of the cell cycle at multiple checkpoints coupled with an increase in senescence - but not apoptosis - compared to single agent treatments. Importantly we find synergistic increase in senescence even in resistant models when rechallenged in combination with MDM2 inhibition compared to MDM2 inhibition alone.

  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 in combination with standard of care therapy.