Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer
Sungsoo Kim,
Jessica Armand,
Anton Safonov,
Mimi Zhang,
Rajesh K. Soni,
Gary Schwartz,
Julia E. McGuinness,
Hanina Hibshoosh,
Pedram Razavi,
Minah Kim,
Sarat Chandarlapaty,
Hee Won Yang
Affiliations
Sungsoo Kim
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
Jessica Armand
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
Anton Safonov
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Mimi Zhang
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
Rajesh K. Soni
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
Gary Schwartz
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA
Julia E. McGuinness
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA
Hanina Hibshoosh
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
Pedram Razavi
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA
Minah Kim
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
Sarat Chandarlapaty
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Hee Won Yang
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Corresponding author
Summary: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels.
