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

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.

Downregulation of PLK4 expression induces apoptosis and G0/G1‐phase cell cycle arrest in keloid fibroblasts

“…17,52,53 As a critical regulator of cancer development, PLK4 has emerged as a therapeutic target for multiple cancers. 42,43,56 PLK4 inhibitors, such as CFI-400945, 15 centrinone, 57,58 Cen-B, 27,59 YLZ-F5, 26 and YLT-11, 25 have shown anticancer effects in multiple cancers. In this study, Cen-B, a potent and highly selective PLK4 inhibitor, 60 In summary, we reported herein that keloids expressed high levels of PLK4, which induced tumor-like malignant biological behaviors in KFs, including enhanced proliferation, migration, and invasion.…”

“… 10 The PLK4 enzyme is expressed at low levels in proliferating tissues and has pleiotropic functions in processes related to mitotic progression, including cytokinesis, cell mobility, and DNA damage repair. 11 , 12 Increasing evidence indicates that PLK4 is aberrantly expressed in patient‐derived tumor samples, including colorectal cancer, 13 , 14 breast cancer, 15 , 16 bladder cancer, 17 and melanoma, 18 but is also expressed at low levels in proliferative tissues. 19 , 20 , 21 However, its expression level differs among cancers and proliferative tissues.…”

“… 22 , 23 Blockade of PLK4 by selective small‐molecule inhibitors or RNA interference impairs centriole duplication, enhances genomic instability, and ultimately causes mitotic defects and cell death. 24 In addition, inhibition of PLK4 by small‐molecule inhibitors, including CFI‐400945, YLT‐11, and centrinone B (Cen‐B), could suppress tumor growth 25 , 26 or increase sensitivity to radiation 15 , 27 and chemotherapy. 28 , 29 Due to its key role in tumor growth and development, PLK4 is considered one of the most promising therapeutic targets in cancer.…”

Targeted Therapeutic Strategies for Triple-Negative Breast Cancer

“…PLK4 inhibitors would potentiate aneuploidy and genomic instability and lead to cancer cell death (102). An in vitro experimental study showed that a novel inhibitor of PLK4, CFI-400945, in combination with radiation, exhibited a synergistic anticancer effect in TNBC cell lines and patient-derived organoids and led to a significant increase in survival to tumor endpoint in xenograft models in vivo, compared to control or single-agent treatment (44). However, overactivation of PLK4 is always correlated with centrosome amplification (CA) promoting a high risk of breast cancer (103).…”

3D Breast Tumor Models for Radiobiology Applications

“…Irradiated nanoparticles enhance the dose deposited locally by producing secondary electrons that add to ROS production and DNA damage within the cell [ 56 ]. Another important strategy has been to repurpose already known small molecule inhibitors and chemotherapeutic drugs to complement irradiation and function as radiosensitizers [ 59 , 60 , 61 , 62 ]. In a recent study, Speers et al analyzed the radiation responses of 21 breast cancer cell lines using a high-throughput novel drug radiosensitivity screen where the androgen receptor was identified as the optimal target for radiosensitization [ 63 ].…”