PLK1 overexpression suppresses homologous recombination and confers cellular sensitivity to PARP inhibition DOI Creative Commons

Sookhee Pae,

Anna S. Sedukhina,

Runa Sugiyama

и другие.

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Дек. 28, 2024

The overexpression of Polo-like kinase 1 (PLK1) is associated with poor clinical outcomes in various malignancies, making it an attractive target for anticancer therapies. Although recent studies suggest PLK1's involvement homologous recombination (HR), the impact its on HR remains unclear. In this study, we investigated effect PLK1 using bioinformatics and experimental approaches. Analyzing Cancer Genome Atlas (TCGA) Cell Line Encyclopedia (CCLE) datasets Homologous Recombination Deficiency (HRD) score, found a positive correlation between expression HRD indicating that increased suppresses HR. To validate these findings, performed cell line-based experiments, demonstrating attenuates RAD51 focus formation HR, as measured by ASHRA T47D cells. Since HR-deficient cells are hypersensitive to PARP inhibitors, further confirmed increases sensitivity both CCLE dataset analysis experiments Additionally, effects suppression inhibitor were mitigated either or kinase-dead mutant [T210A]. This suggests mediated through activity. Moreover, ovarian cancer samples revealed higher correlates inhibitors. Our results recombination, leading enhanced inhibition, presenting potential therapeutic strategy targeting cancers PLK1.

Язык: Английский

Homologous Recombination Deficiency Unrelated to Platinum and PARP Inhibitor Response in Cell Line Libraries DOI Creative Commons
Shiro Takamatsu, Kosuke Murakami, Noriomi Matsumura

и другие.

Scientific Data, Год журнала: 2024, Номер 11(1)

Опубликована: Фев. 6, 2024

Abstract While large publicly available cancer cell line databases are invaluable for preclinical drug discovery and biomarker development, the association between homologous recombination deficiency (HRD) sensitivity in these resources remains unclear. In this study, we comprehensively analyzed molecular profiles screening data from Cancer Cell Line Encyclopedia. Unexpectedly, gene alterations BRCA1/2 or recombination-related genes, HRD scores, mutational signature 3 were not positively correlated with to platinum agents PARP inhibitors. Rather, higher scores significantly associated resistance multiple assays. These findings consistent when analyzing exclusively breast ovarian lines using COSMIC Project. Collectively, existing established do reflect expected status response inhibitors clinical tumors. This discrepancy may extend other tumor characteristics, highlighting importance of recognizing potential limitations researchers.

Язык: Английский

Процитировано

8
Homologous recombination deficiency: a reliable biomarker or a misleading indicator? DOI Creative Commons
Hisamitsu Takaya, Shiro Takamatsu, Hidekatsu Nakai

и другие.

Expert Review of Molecular Diagnostics, Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Язык: Английский

Процитировано

0
An interpretable deep learning framework for genome-informed precision oncology DOI
Shuangxia Ren, Gregory F. Cooper, Lujia Chen

и другие.

Nature Machine Intelligence, Год журнала: 2024, Номер 6(8), С. 864 - 875

Опубликована: Июль 11, 2024

Язык: Английский

Процитировано

1
Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecological Cancers DOI Creative Commons
Marwa W. Aljardali, Kevin M. Kremer, Jessica E. Parker

и другие.

Cancer Research Communications, Год журнала: 2024, Номер 4(6), С. 1495 - 1504

Опубликована: Май 20, 2024

Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth some cancers irrespective their status, suggesting alternative mechanisms action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase localizes nucleoli and is a target PARP1. have now extended this observation endometrial ovarian provided links patient outcomes. When PARP1-mediated ADPRylation DDX21 inhibited by niraparib, mislocalized nucleoplasm resulting decreased rDNA transcription, which leads reduction ribosome biogenesis, protein translation, ultimately cell growth. High PARP1 expression was associated high nucleolar localization both cancers. negatively correlated calculated IC50s for niraparib. By studying samples, we were able show significantly survival. Our study suggests use as therapeutic be expanded further types potentially used prognostic factor biomarker response PARPi.

Язык: Английский

Процитировано

0
Pan-cancer Analysis of Homologous Recombination Deficiency in Cell Lines DOI Creative Commons
Anne E. Dodson, Sol Shenker,

Pamela Sullivan

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 20, 2024

ABSTRACT Homologous Recombination Deficiency (HRD) drives genomic instability in multiple cancer types and renders tumors vulnerable to certain DNA damaging agents such as PARP inhibitors. Thus, HRD is emerging an attractive biomarker oncology. A variety of silico methods are available for predicting HRD; however, few these have been applied cell lines a comprehensive manner. Here we utilized two methods, “CHORD” “HRDsum” scores, predict 1,332 84 non-cancerous lines. Cell with biallelic mutations BRCA1 or BRCA2 , which encode key components the homologous recombination pathway, showed strongest predictions, validating small subset BRCA1/2 -wildtype were also classified HRD, several evidence epigenetic silencing. Similar patient samples, was associated p53 loss, mutually exclusive microsatellite occurred most frequently breast ovarian types. In addition previously identified associations leveraged line-specific datasets gain new insights into its relation various genetic dependency drug sensitivity profiles. We found that lines, inhibition cancer, but not at pan-cancer level. By generating large-scale, on predictions aim facilitate efforts improve our understanding utility biomarker. SIGNIFICANCE STATEMENT common can be exploited therapeutically, it sensitizes cells agents. scored over 1,300 using different bioinformatic approaches, thereby enabling large-scale analyses provide insight etiology features HRD.

Язык: Английский

Процитировано

0
PLK1 overexpression suppresses homologous recombination and confers cellular sensitivity to PARP inhibition DOI Creative Commons

Sookhee Pae,

Anna S. Sedukhina,

Runa Sugiyama

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 27, 2024

Abstract The overexpression of Polo-like kinase 1 (PLK1) is linked to poor clinical outcomes in various malignancies, making it an attractive target for anticancer therapies. Although recent studies suggest PLK1's involvement homologous recombination (HR), the impact its on HR remains unclear. We investigated effect PLK1 using bioinformatics and experimental approaches. Analyzing Cancer Genome Atlas (TCGA) Cell Line Encyclopedia (CCLE) datasets with Homologous Recombination Deficiency (HRD) score, we found a positive correlation between expression HRD indicating that increased suppresses HR. To validate these findings, performed cell line-based experiments, demonstrating attenuates RAD51 focus formation HR, as measured by ASHRA U2OS cells. Given HR-deficient cells display hypersensitivity PARP inhibitors, further confirmed increases sensitivity both CCLE dataset analysis experiments Additionally, ovarian cancer samples revealed higher correlates inhibitors. Our results recombination, leading enhanced inhibition, presenting potential therapeutic strategy targeting cancers PLK1.

Язык: Английский

Процитировано

0
Characterization of DNA damage repair pathway utilization in high-grade serous ovarian cancers yields rational therapeutic approaches DOI Creative Commons

Erika Nakatsuka,

Lijun Tan,

Brianna P. Cunneen

и другие.

Translational Oncology, Год журнала: 2024, Номер 50, С. 102119 - 102119

Опубликована: Сен. 12, 2024

Язык: Английский

Процитировано

0
PLK1 overexpression suppresses homologous recombination and confers cellular sensitivity to PARP inhibition DOI Creative Commons

Sookhee Pae,

Anna S. Sedukhina,

Runa Sugiyama

и другие.

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Дек. 28, 2024

The overexpression of Polo-like kinase 1 (PLK1) is associated with poor clinical outcomes in various malignancies, making it an attractive target for anticancer therapies. Although recent studies suggest PLK1's involvement homologous recombination (HR), the impact its on HR remains unclear. In this study, we investigated effect PLK1 using bioinformatics and experimental approaches. Analyzing Cancer Genome Atlas (TCGA) Cell Line Encyclopedia (CCLE) datasets Homologous Recombination Deficiency (HRD) score, found a positive correlation between expression HRD indicating that increased suppresses HR. To validate these findings, performed cell line-based experiments, demonstrating attenuates RAD51 focus formation HR, as measured by ASHRA T47D cells. Since HR-deficient cells are hypersensitive to PARP inhibitors, further confirmed increases sensitivity both CCLE dataset analysis experiments Additionally, effects suppression inhibitor were mitigated either or kinase-dead mutant [T210A]. This suggests mediated through activity. Moreover, ovarian cancer samples revealed higher correlates inhibitors. Our results recombination, leading enhanced inhibition, presenting potential therapeutic strategy targeting cancers PLK1.

Язык: Английский

Процитировано

0