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Review
. 2024 Jan 29:14:1307839.
doi: 10.3389/fonc.2024.1307839. eCollection 2024.

Targeting the DNA damage response in hematological malignancies

Sanjay De Mel  1   2   3 , Ainsley Ryan Lee  2 , Joelle Hwee Inn Tan  2 , Rachel Zi Yi Tan  4 , Li Mei Poon  1   3 , Esther Chan  1   3 , Joanne Lee  1   3 , Yen Lin Chee  1   3 , Satish R Lakshminarasappa  5 , Patrick William Jaynes  4 , Anand D Jeyasekharan  1   2   3   4
Affiliations
Review

Targeting the DNA damage response in hematological malignancies

Sanjay De Mel et al. Front Oncol. .

Abstract

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.

Keywords: DNA damage; clinical trials; combination therapy; haematologic malignancies; inhibitors.

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Conflict of interest statement

AJ has received consultancy fees from Roche, Gilead, Turbine Ltd, AstraZeneca, Antegene, Janssen, MSD and IQVIA; and research funding from Janssen and AstraZeneca. SD has been on advisory boards for Amgen and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic summarizing the DDR is tested pre-clinically across all haematological malignancies. Created with BioRender.com.
See this image and copyright information in PMC

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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Work in AJ’s laboratory is funded by a core grant from the Cancer Science Institute of Singapore, National University of Singapore through the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.

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