Anticancer effects of radiation therapy combined with Polo-Like Kinase 4 (PLK4) inhibitor CFI-400945 in triple negative breast cancer
Armen Parsyan,
Jennifer Cruickshank,
Kelsey Hodgson,
Drew Wakeham,
Sierra Pellizzari,
Vasudeva Bhat,
David W. Cescon
Affiliations
Armen Parsyan
Department of Surgery, St Joseph’s Health Care and London Health Sciences Centre, Western University, London, Ontario, N6A 4V2, Canada; Department of Oncology, Western University, London, Ontario, N6A 5W9, Canada; London Regional Cancer Program, London Health Sciences Centre, Western University, London, Ontario, N6A 5W9, Canada; Department of Anatomy and Cell Biology, London Regional Cancer Program, Western University, London, Ontario, N6A 5C1, Canada; Corresponding author. 268 Grosvenor St, D1-204, London, Ontario, N6A 4V2, Canada.
Jennifer Cruickshank
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
Kelsey Hodgson
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
Drew Wakeham
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
Sierra Pellizzari
Department of Anatomy and Cell Biology, London Regional Cancer Program, Western University, London, Ontario, N6A 5C1, Canada
Vasudeva Bhat
London Regional Cancer Program, London Health Sciences Centre, Western University, London, Ontario, N6A 5W9, Canada; Department of Anatomy and Cell Biology, London Regional Cancer Program, Western University, London, Ontario, N6A 5C1, Canada
David W. Cescon
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
Development of novel multimodality radiotherapy treatments in metastatic breast cancer, especially in the most aggressive triple negative (TNBC) subtype, is of significant clinical interest. Here we show that a novel inhibitor of Polo-Like Kinase 4 (PLK4), CFI-400945, in combination with radiation, exhibits a synergistic anti-cancer effect in TNBC cell lines and patient-derived organoids in vitro and leads to a significant increase in survival to tumor endpoint in xenograft models in vivo, compared to control or single-agent treatment. Further preclinical and proof-of-concept clinical studies are warranted to characterize molecular mechanisms of action of this combination and its potential applications in clinical practice.
