Physical Poster + E-Poster Presentation 34th Lorne Cancer Conference 2022

Overcoming CDK4/6 inhibitor resistance in breast cancer by CDK1 targeting revealed by the CDK1-FRET mouse (#257)

Max Nobis 1 , Clare Zhang 1 , Janett Stoehr 1 , Kristine Fernandez 1 , Sarah Alexandrou 1 , Christine Lee 1 , Victoria Lee 1 , Cris S Guaman 1 , Astrid Magenau 1 , Aliza Yong 1 , Tim Lam 1 , Daniel R Reed 1 , Sharissa L Latham 1 , Neil Portman 1 , David Herrmann 1 , Sandra O'Toole 2 3 , Alex Swarbrick 1 , Yangxiao Wang 4 , Douglas Strathdee 5 6 , Owen J Sansom 5 6 , Jennifer P Morton 5 6 , Elgene Lim 1 , Paul Timpson 1 , Catherine E Caldon 1
  1. The Garvan Institute of Medical Research, St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
  2. Sydney Medical School, Sydney University, Sydney, NSW, Australia
  3. Department of Tissue, Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
  4. Department of Bioengineering and Institute of Engineering in Medicine, University of California, San DIego, CA, USA
  5. Cancer Research UK Beatson Institute, Glasgow, Lanarkshire, UK
  6. Institute of Cancer Sciences, University of Glasgow, Glasgow, Lanarkshire, UK

CDK4/6 inhibitors such as Ribociclib are becoming new standard-of-care for advanced estrogen receptor positive (ER+) breast cancer, however, patients inevitably progress with acquired CDK4/6 resistance. Since this is often the last line of therapy for many breast cancer patients, it is critical to elucidate and target factors involved in CDK4/6 inhibitor resistance.

Here we show that the CDK1/cyclinB1 complex is upregulated in ER+ breast cancer and associated with poorer survival in patients. CDK1 and phospho-CDK1 is further found to be spatially expressed in MMTV-PyMT hyperplasias, adenomas, carcinomas and metastasis of the lung. Using a CDK1-FRET biosensor mouse we were able to map CDK1 activity within the primary tumour and lung metastasis. Cell lines resistant to standard-of-care therapy Tamoxifen and CDK4/6 inhibitor Ribociclib were established and treatment with the Ribociclib in conjunction to the CDK1 inhibitor RO-3306 and the pan-CDK inhibitor Dinaciclib respectively showed profound synergy. This was also explored in a 3D context of invading PyMT cells on organotypic matrices. Using intravital imaging of MMTV-PyMT mice expressing the CDK1-FRET biosensor we were able to demonstrate spatiotemporal upregulation of CDK1 following CDK4/6 inhibition. Patient derived xenografts (PDX) of treatment naïve and hormone therapy resistant tumours were made resistant to CDK4/6 inhibitors in mice and these tumours displayed high levels of CDK1 and phospho-CDK1. Treatment of these treatment resistant PDX tumours with the clinically relevant inhibitor Dinaciclib resulted in a strong reduction of tumour growth.

In conclusion, targeting of CDK1 in a CDK4/6 inhibitor resistant setting is developing to be a promising new treatment modality in the difficult to treat, resistant and relapsed ER+ breast cancer tumour setting.