Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer.

Wiegmans, Adrian P; Ward, Ambber; Ivanova, Ekaterina; Duijf, Pascal H G; Adams, Mark N; Najib, Idris Mohd; Van Oosterhout, Romy; Sadowski, Martin C; Kelly, Greg; Morrical, Scott W; O'Byrne, Ken; Lee, Jason S; Richard, Derek J (2021). Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer. NAR cancer, 3(2), zcab022. Oxford University Press 10.1093/narcan/zcab022

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Chemotherapy is used as a standard-of-care against cancers that display high levels of inherent genome instability. Chemotherapy induces DNA damage and intensifies pressure on the DNA repair pathways that can lead to deregulation. There is an urgent clinical need to be able to track the emergence of DNA repair driven chemotherapy resistance and tailor patient staging appropriately. There have been numerous studies into chemoresistance but to date no study has elucidated in detail the roles of the key DNA repair components in resistance associated with the frontline clinical combination of anthracyclines and taxanes together. In this study, we hypothesized that the emergence of chemotherapy resistance in triple negative breast cancer was driven by changes in functional signaling in the DNA repair pathways. We identified that consistent pressure on the non-homologous end joining pathway in the presence of genome instability causes failure of the key kinase DNA-PK, loss of p53 and compensation by p73. In-turn a switch to reliance on the homologous recombination pathway and RAD51 recombinase occurred to repair residual double strand DNA breaks. Further we demonstrate that RAD51 is an actionable target for resensitization to chemotherapy in resistant cells with a matched gene expression profile of resistance highlighted by homologous recombination in clinical samples.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Sadowski, Martin

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2632-8674

Publisher:

Oxford University Press

Language:

English

Submitter:

Christa Hagert

Date Deposited:

06 Dec 2021 10:48

Last Modified:

06 Dec 2021 10:48

Publisher DOI:

10.1093/narcan/zcab022

PubMed ID:

34316709

BORIS DOI:

10.48350/161794

URI:

https://boris.unibe.ch/id/eprint/161794

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