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.

Keywords: BOD1L; Double strand break repair; H3K4; PARP inhibitor; SETD1A; histone methylation; resistance.

Figure 1

Effects of BOD1L/SETD1A loss on PARP inhibitor sensitivity in BRCA1-deficient cells. (A) H3K4me mediated by the BOD1L/SETD1A complex promotes RIF1 localisation at DNA double-strand breaks (DSBs) and stimulates NHEJ. In BRCA1-deficient cells, DNA-end resection and RAD51 loading are inhibited and lesions cannot be repaired by homologous recombination (HR), resulting in sensitivity to PARP inhibition and cell death. (B) Depletion of the BOD1L/SETD1A complex results in loss of H3K4me and decreased RIF1 localisation to DSBs. This allows DNA end-resection and RAD51 loading, partially restoring HR. This mediates resistance to PARP inhibition and allows cells to survive. Me: Methylation; PARP: poly(ADP) ribose polymerase; NHEJ: non-homologous end joining; KDMs: lysine demethylases.

Figure 2

Future strategies to restore PARP inhibitor efficacy in BRCA1-deficient cells upon loss of SETD1A function. Sensitivity to PARP inhibition following loss of the BOD1L/SETD1A complex or H3K4me perturbation could potentially be restored via 3 mechanisms including: (1) inhibition of the lysine demethylases (KMD5 and LSD1) responsible for removing H3K4me; (2) inhibiting nucleases such as MRE11 to prevent DNA-end resection which facilitates HR; and (3) exploiting collateral vulnerabilities using chemotherapeutics, e.g., cisplatin. Me: Methylation; PARP: poly(ADP) ribose polymerase; HR: homologous recombination; NHEJ: non-homologous end joining; DSB: double-strand break; KDMs: lysine demethylases.