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Lookup NU author(s): Dr Sweta Sharma SahaORCiD, Lucy Gentles, Dominik Brecht, Dr Rachel O'DonnellORCiD, Professor Nicola CurtinORCiD, Dr Yvette DrewORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 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.
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
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