New perspectives on epigenetic modifications and PARP inhibitor resistance in HR-deficient cancers

Rachel Bayley; Ellie Sweatman; Martin Higgs

doi:10.20517/cdr.2022.73

New perspectives on epigenetic modifications and PARP inhibitor resistance in HR-deficient cancers

Rachel Bayley, Ellie Sweatman, Martin Higgs^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ribose polymerase (PARP) inhibitors. However, the efficacy of these compounds is hampered by resistance, which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage. Here, we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance. We discuss the implications, with a particular focus on epigenetic modifications and H3K4 methylation. We also deliberate on the mechanisms responsible, the consequences for the refinement of PARP inhibitor use in the clinic, and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.

Original language	English
Pages (from-to)	35-44
Number of pages	10
Journal	Cancer drug resistance (Alhambra, Calif.)
Volume	6
DOIs	https://doi.org/10.20517/cdr.2022.73
Publication status	Published - 4 Jan 2023

Keywords

Double strand break repair
histone methylation
PARP inhibitor
resistance
SETD1A
BOD1L
H3K4

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.20517/cdr.2022.73Licence: Creative Commons: Attribution (CC BY)

BayleyR2023NewFinal published version, 783 KBLicence: Creative Commons: Attribution (CC BY)

The impact of non-histone protein methylation by set1a in maintaining genome stability and preventing disease
Higgs, M. (Principal Investigator)
Medical Research Council
1/04/17 → 31/03/23
Project: Research Councils

Cite this

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title = "New perspectives on epigenetic modifications and PARP inhibitor resistance in HR-deficient cancers",

abstract = "The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ribose polymerase (PARP) inhibitors. However, the efficacy of these compounds is hampered by resistance, which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage. Here, we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance. We discuss the implications, with a particular focus on epigenetic modifications and H3K4 methylation. We also deliberate on the mechanisms responsible, the consequences for the refinement of PARP inhibitor use in the clinic, and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.",

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AU - Sweatman, Ellie

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N2 - The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ribose polymerase (PARP) inhibitors. However, the efficacy of these compounds is hampered by resistance, which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage. Here, we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance. We discuss the implications, with a particular focus on epigenetic modifications and H3K4 methylation. We also deliberate on the mechanisms responsible, the consequences for the refinement of PARP inhibitor use in the clinic, and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.

AB - The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ribose polymerase (PARP) inhibitors. However, the efficacy of these compounds is hampered by resistance, which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage. Here, we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance. We discuss the implications, with a particular focus on epigenetic modifications and H3K4 methylation. We also deliberate on the mechanisms responsible, the consequences for the refinement of PARP inhibitor use in the clinic, and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.

KW - Double strand break repair

KW - histone methylation

KW - PARP inhibitor

KW - resistance

KW - SETD1A

KW - BOD1L

KW - H3K4

U2 - 10.20517/cdr.2022.73

DO - 10.20517/cdr.2022.73

M3 - Article

SN - 2578-532X

VL - 6

SP - 35

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JO - Cancer drug resistance (Alhambra, Calif.)

JF - Cancer drug resistance (Alhambra, Calif.)

ER -

New perspectives on epigenetic modifications and PARP inhibitor resistance in HR-deficient cancers

Abstract

Keywords

UN SDGs

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The impact of non-histone protein methylation by set1a in maintaining genome stability and preventing disease

Cite this