Dataset Information

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.

SUBMITTER: Parsyan A

PROVIDER: S-EPMC8079282 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Parsyan Armen A Cruickshank Jennifer J Hodgson Kelsey K Wakeham Drew D Pellizzari Sierra S Bhat Vasudeva V Cescon David W DW

Breast (Edinburgh, Scotland) 20210401

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, compa ...[more]

PMID: 33866248

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Project description:RAPTA-EA1 is a promising glutathione transferase (GSTP-1) inhibitor that has previously been shown to inhibit the growth of various breast cancer cells. We studied the anticancer activity of RAPTA-EA1 on triple-negative BRCA1 competent breast cancer MDA-MB-231 cells. MDA-MB-231 cells are significantly more sensitive to RAPTA-EA1 than MCF-7 cells. Treatment reveals a higher degree of cytotoxicity than cisplatin against both cell lines. Ruthenium accumulation in MDA-MB-231 cells is mainly in the nuclear fraction (43%), followed by the cytoplasm (30%), and the mitochondria (27%). RAPTA-EA1 blocks cell growth at the G2/M phase, leading to nuclear condensation and cell death. The compound slightly inhibits DNA replication of the 3,426-bp fragment of the BRCA1 exon 11 of the cells, with approximately 0.6 lesion per the BRCA1 fragment. The expression of BRCA1 mRNA and its protein in the Ru-treated cells is curtailed by 50-80% compared to the untreated controls. Growth inhibition of the triple-negative BRCA1 wild-type MDA-MB-231 and the sporadic BRCA1 wild-type MCF-7 cells by olaparib (a poly [ADP-ribose] polymerase (PARP) inhibitor) is dose-dependent, with MDA-MB-231 cells being two-fold less susceptible to the drug than MCF-7 cells. Combining olaparib with RAPTA-EA1 results in a combination index (CI) of 0.78 (almost additive) in MDA-MB-231 cells and 0.24 (potent synergy) in the MCF-7 cells. The PARP inhibitor alone differently regulates the expression of BRCA1 mRNA in both cell lines, whereas the olaparib-RAPTA-EA1 combination induces overexpression of BRCA1 mRNA in these cells. However, the expression level of the BRCA1 protein is dramatically reduced after treatment with the combined inhibitors, compared with the untreated controls. This observation highlights the cellular responses of triple-negative BRCA1 proficient breast cancer MDA-MB-231 cells to RAPTA-EA1 through BRCA1 inhibition and provides insights into alternative treatments for breast cancer.

Dataset Information

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

Publications

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

Similar Datasets

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