Combined inhibition of PARP and EZH2 for cancer treatment: Current status, opportunities, and challenges

Abstract

Tumors with BRCA1/2 mutations or homologous recombination repair defects are sensitive to PARP inhibitors through the mechanism of synthetic lethality. Several PARP inhibitors are currently approved for ovarian, breast and pancreatic cancer in clinical practice. However, more than 40% of patients with BRCA1/2 mutations are insensitive to PARP inhibitors, which has aroused attention to the mechanism of PARP resistance and sensitization schemes. PARP inhibitor resistance is related to homologous recombination repair, stability of DNA replication forks, PARylation and epigenetic modification. Studies on epigenetics have become the hotspots of research on PARP inhibitor resistance. As an important epigenetic regulator of transcription mediated by histone methylation, EZH2 interacts with PARP through DNA homologous recombination, DNA replication, posttranslational modification, tumor immunity and other aspects. EZH2 inhibitors have been just shifting from the bench to the bedside, but the combination scheme in cancer therapy has not been fully explored yet. Recently, a revolutionary drug design combining PARP inhibitors and EZH2 inhibitors based on PROTAC techniques has shed light on the resolution of PARP inhibitor resistance. This review summarizes the interactions between EZH2 and PARP, suggests the potential PARP inhibitor sensitization effect of EZH2 inhibitors, and further discusses the potential populations that benefit from the combination of EZH2 inhibitors and PARP inhibitors.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis

“…Recently, PROTACs [ 22 ] have been developed for inhibiting EZH2 [ 37 , 54 , 55 ]. PROTACs are advantageous due to their high activity, low toxicity, broad target specificity, and ability to overcome challenges posed by target gene mutations [ 56 ].…”

Clinical application of PARP inhibitors in ovarian cancer: from molecular mechanisms to the current status

“…EZH2 inhibitors up-regulate the permeability of immune cells in tumor microenvironment and induce reprogramming of immunosuppressive cells, thus enhancing the killing effect of PARP inhibitors on tumor cells. However, the combination of these two drugs will also disrupt the immune microenvironment of tumors, and in different tumors and different molecular types of tumors, the combination of the two drugs needs to be further explored [ 95 ].…”

Identification of Potential Biomarkers associated with Prognosis and Pathogenesis of Pancreatic Cancer

“…Furthermore, the combination of MEK inhibitors and STAT3 inhibitors relieve mesenchymal in ammation and enriches the CAF phenotype with MSC-like properties, overcoming immunotherapy resistance in PDAC [53].EZH2 is one of the most important epigenetic factors involved in the regulation of tumourigenesis, progression and metastasis, and is highly expressed in various tumours. The typical pathway by which EZH2 promotes cancer is catalytic trimethylation of histone H3K27 to silence the transcription of target genes and the atypical pathway is non-histone methylation and even transcriptional activation and interaction with other TFs [54]. Tumours with high expression of EZH2 tend to have a poor prognosis.…”