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.