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

doi:10.1016/j.celrep.2018.03.039

Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer

Cell Rep. 2018 Apr 3;23(1):112-126. doi: 10.1016/j.celrep.2018.03.039.

Authors

Jeff C Liu¹, Letizia Granieri², Mariusz Shrestha³, Dong-Yu Wang¹, Ioulia Vorobieva³, Elizabeth A Rubie⁴, Rob Jones¹, YoungJun Ju¹, Giovanna Pellecchia⁵, Zhe Jiang¹, Carlo A Palmerini⁶, Yaacov Ben-David⁷, Sean E Egan⁸, James R Woodgett⁴, Gary D Bader⁹, Alessandro Datti¹⁰, Eldad Zacksenhaus¹¹

Affiliations

¹ Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1.
² 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.
³ 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.
⁴ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, ON, Canada.
⁵ The Donnelly Centre, University of Toronto, Toronto, ON, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Agriculture, Food, and Environmental Sciences, University of Perugia, Perugia, Italy.
⁷ 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.
⁸ 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.
⁹ The Donnelly Centre, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ 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.
¹¹ 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. Electronic address: eldad.zacksenhaus@utoronto.ca.

Abstract

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.

Keywords: CDC25; CHK1; PTEN; RB1; TP53; WEE1; basal-like breast cancer; checkpoint control; therapy; triple negative breast cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Cell Proliferation / drug effects
Enzyme Inhibitors / pharmacology*
Enzyme Inhibitors / therapeutic use
Female
Humans
Mice
Mice, Inbred NOD
Mice, SCID
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Retinoblastoma Binding Proteins / genetics
Retinoblastoma Binding Proteins / metabolism
Triple Negative Breast Neoplasms / drug therapy*
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
cdc25 Phosphatases / antagonists & inhibitors*
cdc25 Phosphatases / genetics
cdc25 Phosphatases / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
Retinoblastoma Binding Proteins
Tumor Suppressor Protein p53
cdc25 Phosphatases
PTEN Phosphohydrolase

Abstract

Publication types

MeSH terms

Substances

Grants and funding