Replication Fork Remodeling and Therapy Escape in DNA Damage Response-Deficient Cancers

Most cancers have lost a critical DNA damage response (DDR) pathway during tumor evolution. These alterations provide a useful explanation for the initial sensitivity of tumors to DNA-targeting chemotherapy. A striking example is dysfunctional homology-directed repair (HDR), e.g., due to inactivatin...

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Published in:Frontiers in oncology Vol. 10; p. 670
Main Authors: Liptay, Martin, Barbosa, Joana S., Rottenberg, Sven
Format: Journal Article
Language:English
Published: Switzerland Frontiers Media S.A 05.05.2020
Subjects:
chemotherapy
DNA damage response
DNA damage tolerance
DNA replication
drug resistance
Oncology
replication fork
BRCA1/2
DNA damage tolerance
DNA replication
DNA damage response
PARP inhibitors
replication fork
drug resistance
chemotherapy
ISSN:2234-943X, 2234-943X
Online Access:Get full text
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Summary:Most cancers have lost a critical DNA damage response (DDR) pathway during tumor evolution. These alterations provide a useful explanation for the initial sensitivity of tumors to DNA-targeting chemotherapy. A striking example is dysfunctional homology-directed repair (HDR), e.g., due to inactivating mutations in and genes. Extensive efforts are being made to develop novel targeted therapies exploiting such an HDR defect. Inhibitors of poly(ADP-ribose) polymerase (PARP) are an instructive example of this approach. Despite the success of PARP inhibitors, the presence of primary or acquired therapy resistance remains a major challenge in clinical oncology. To move the field of precision medicine forward, we need to understand the precise mechanisms causing therapy resistance. Using preclinical models, various mechanisms underlying chemotherapy resistance have been identified. Restoration of HDR seems to be a prevalent mechanism but this does not explain resistance in all cases. Interestingly, some factors involved in DNA damage response (DDR) have independent functions in replication fork (RF) biology and their loss causes RF instability and therapy sensitivity. However, in BRCA-deficient tumors, loss of these factors leads to restored stability of RFs and acquired drug resistance. In this review we discuss the recent advances in the field of RF biology and its potential implications for chemotherapy response in DDR-defective cancers. Additionally, we review the role of DNA damage tolerance (DDT) pathways in maintenance of genome integrity and their alterations in cancer. Furthermore, we refer to novel tools that, combined with a better understanding of drug resistance mechanisms, may constitute a great advance in personalized diagnosis and therapeutic strategies for patients with HDR-deficient tumors.
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Edited by: Christian Reinhardt, University of Cologne, Germany
Reviewed by: Zhi-Xiang Xu, University of Alabama at Birmingham, United States; Alvaro Galli, Italian National Research Council, Italy
This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology
These authors have contributed equally to this work
ISSN:2234-943X
2234-943X
DOI:10.3389/fonc.2020.00670