Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer
Jeff C. Liu,
Letizia Granieri,
Mariusz Shrestha,
Dong-Yu Wang,
Ioulia Vorobieva,
Elizabeth A. Rubie,
Rob Jones,
YoungJun Ju,
Giovanna Pellecchia,
Zhe Jiang,
Carlo A. Palmerini,
Yaacov Ben-David,
Sean E. Egan,
James R. Woodgett,
Gary D. Bader,
Alessandro Datti,
Eldad Zacksenhaus
Affiliations
Jeff C. Liu
Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1
Letizia Granieri
Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1; Department of Agriculture, Food, and Environmental Sciences, University of Perugia, Perugia, Italy
Mariusz Shrestha
Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada
Dong-Yu Wang
Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1
Ioulia Vorobieva
Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada
Elizabeth A. Rubie
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, ON, Canada
Rob Jones
Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1
YoungJun Ju
Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1
Giovanna Pellecchia
The Donnelly Centre, University of Toronto, Toronto, ON, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
Zhe Jiang
Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1
Carlo A. Palmerini
Department of Agriculture, Food, and Environmental Sciences, University of Perugia, Perugia, Italy
Yaacov Ben-David
The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou 550014, China; State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou 550025, China
Sean E. Egan
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada
James R. Woodgett
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, ON, Canada
Gary D. Bader
The Donnelly Centre, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
Alessandro Datti
Department of Agriculture, Food, and Environmental Sciences, University of Perugia, Perugia, Italy; Network Biology Collaborative Centre, SMART Laboratory for High-Throughput Screening Programs, Mount Sinai Hospital, Toronto, ON, Canada
Eldad Zacksenhaus
Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Corresponding author
Summary: CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC), RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition. Minimal cooperation was observed in vitro between CDC25 antagonists and CDK1, CDK2, or CDK4/6 inhibitors, but strong synergy with WEE1 inhibition was apparent. In accordance with increased PI3K signaling following long-term CDC25 inhibition, CDC25 and PI3K inhibitors effectively synergized to suppress TNBC growth both in vitro and in xenotransplantation models. These results provide a rationale for the development of CDC25-based therapies for diverse RB1/PTEN/TP53-deficient and -proficient TNBCs. : Liu et al. report that inhibition of the protein phosphatase CDC25 kills diverse triple-negative breast cancer (TNBC) cells. Moreover, CDC25 antagonists cooperate with other drugs, such as PI3K inhibitors, to efficiently suppress growth of human TNBC engrafted into mice. Keywords: triple negative breast cancer, basal-like breast cancer, therapy, RB1, PTEN, TP53, CDC25, WEE1, CHK1, checkpoint control
