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Genomic, transcriptomic, and functional alterations in DNA damage response pathways as putative biomarkers of chemotherapy response in ovarian cancer

Lookup NU author(s): Dr Sweta Sharma SahaORCiD, Lucy Gentles, Dominik Brecht, Dr Rachel O'DonnellORCiD, Professor Nicola CurtinORCiD, Dr Yvette DrewORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. Defective DNA damage response (DDR) pathways are enabling characteristics of cancers that not only can be exploited to specifically target cancer cells but also can predict chemotherapy response. Defective Homologous Recombination Repair (HRR) function, e.g., due to BRCA1/2 loss, is a determinant of response to platinum agents and PARP inhibitors in ovarian cancers. Most chemotherapies function by either inducing DNA damage or impacting on its repair but are generally used in the clinic unselectively. The significance of HRR and other DDR pathways in determining response to several other chemotherapy drugs is not well understood. In this study, the genomic, transcriptomic and functional analysis of DDR pathways in a panel of 14 ovarian cancer cell lines identified that defects in DDR pathways could determine response to several chemotherapy drugs. Carboplatin, rucaparib, and topotecan sensitivity were associated with functional loss of HRR (validated in 10 patient-derived primary cultures) and mismatch repair. Two DDR gene expression clusters correlating with treatment response were identified, with PARP10 identified as a novel marker of platinum response, which was confirmed in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Reduced non-homologous end-joining function correlated with increased sensitivity to doxorubicin, while cells with high intrinsic oxidative stress showed sensitivity to gem-citabine. In this era of personalised medicine, molecular/functional characterisation of DDR pathways could guide chemotherapy choices in the clinic allowing specific targeting of ovarian cancers.


Publication metadata

Author(s): Saha SS, Gentles L, Bradbury A, Brecht D, Robinson R, O'Donnell R, Curtin NJ, Drew Y

Publication type: Article

Publication status: Published

Journal: Cancers

Year: 2021

Volume: 13

Issue: 6

Online publication date: 20/03/2021

Acceptance date: 17/03/2021

Date deposited: 08/04/2021

ISSN (electronic): 2072-6694

Publisher: MDPI AG

URL: https://doi.org/10.3390/cancers13061420

DOI: 10.3390/cancers13061420

Data Source Location: https://www.ncbi.nlm.nih.gov/geo/


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Funding

Funder referenceFunder name
MR/N017838
RES/0280/0080

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