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

doi:10.1016/j.breast.2021.03.011

Anticancer effects of radiation therapy combined with Polo-Like Kinase 4 (PLK4) inhibitor CFI-400945 in triple negative breast cancer

Breast. 2021 Aug:58:6-9. doi: 10.1016/j.breast.2021.03.011. Epub 2021 Apr 1.

Authors

Armen Parsyan¹, Jennifer Cruickshank², Kelsey Hodgson², Drew Wakeham², Sierra Pellizzari³, Vasudeva Bhat⁴, David W Cescon⁵

Affiliations

¹ 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. Electronic address: aparsyan@uwo.ca.
² Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada.
³ Department of Anatomy and Cell Biology, London Regional Cancer Program, Western University, London, Ontario, N6A 5C1, Canada.
⁴ 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.
⁵ 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.

Abstract

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.

Keywords: CFI-400945; Patient-derived organoids; Polo-like kinase 4; Radiosensitization; Radiotherapy; Triple-negative breast cancer.

MeSH terms

Cell Line, Tumor
Cell Proliferation
Humans
Indazoles
Indoles
Protein Serine-Threonine Kinases
Triple Negative Breast Neoplasms* / drug therapy
Xenograft Model Antitumor Assays

Substances

2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one
Indazoles
Indoles
PLK4 protein, human
Protein Serine-Threonine Kinases