Efficacy of PARP inhibition combined with EZH2 inhibition depends on BRCA mutation status and microenvironment in breast cancer

Abstract

The efficacy of the combination of a PARP inhibitor (PARPi) and an EZH2 inhibitor has been investigated in breast cancer cells with either BRCA1 mutation or BRCA2 mutation. However, earlier studies focused on the efficacy of this combination against BRCA-mutated but not BRCAproficient breast cancer. Yang et al. observed that PARP1 depletion combined with EZH2 depletion via PRC2 depletion did not affect the growth of BRCA1/2 wild-type breast cancer cells in vitro. Moreover, Yang et al. reported that this combination stimulated synthetic viability of BRCA1/2proficient breast cancer cells in vivo by regulating the tumor microenvironment to induce angiogenesis and differentiation of M2-type macrophages. The findings of Yang et al. provided evidence that both in vitro and animal models should be employed in the studies of PARPi combination therapies in order to involve the alteration of the tumor microenvironment in these investigations. These studies of PARP inhibition combined with EZH2 inhibition in breast cancer showed that this combination may benefit breast cancer patients carrying BRCA1-mutated tumor, but the combination may also enhance recurrence of BRCA2-mutated tumor and may even promote BRCA-proficient cancer cell survival. Therefore, BRCA1 mutation status should be used to select breast cancer patients for PARPi and EZH2 inhibitor combination treatment in clinical trials in the future.

PARP1 as an Epigenetic Modulator: Implications for the Regulation of Host-Viral Dynamics

“…PARP1 inhibition was associated with the increased activity of Polycomb Repressive Complex 2 (PRC2)—a protein complex responsible for the methyltransferase activity of lysine 27 on H3—resulting in decreased condensed chromatin [ 38 ]. Additionally, in BRCA2 proficient cancers, this PARP1-PRC2 interaction has been shown to inhibit NF-kB immune activity [ 39 , 40 , 41 ]. This data would suggest that PARP1 supports transcriptionally activated chromatin through the downregulation of PRC2 activity ( Figure 1 ).…”

Multi-therapies Based on PARP Inhibition: Potential Therapeutic Approaches for Cancer Treatment

“…Recent research revealed that CARM1-high, HR+, and high-grade serous ovarian cancer cells become sensitive to PARP inhibitors in a CARM1-dependent manner and die when EZH2 is functionally silenced . Furthermore, the combination of EZH2 inhibition and PARP inhibition benefited breast cancer patients who carry BRCA1-mutated tumors . Currently, combined application of an EZH2 inhibitor with a PARP inhibitor has been evaluated in ovarian cancer and breast cancer with varying BRCA mutation statuses and has been investigated in clinical trials. − Therefore, dual-target inhibitors with simultaneous inhibition of EZH2 and PARP may offer promising strategies for breast and ovarian cancer treatment.…”

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

“…Currently, experiments and clinical trials raise a question worthy of consideration: which population benefits more from a combination of EZH2 inhibitors and PARP inhibitors? The BRCA mutation state is a distinguishing feature, and the effect of combination rules still relies on the state of BRCA deficiency ( Wicha, 2009 ; Schlacher, 2017 ; Chen, 2021 ); however, studies in ovarian cancer suggest that EZH2 inhibitors sensitize PARP inhibitors in CARM1-high patients and that the CARM1-high population highly overlaps with wild-type BRCA, suggesting that EZH2 inhibitors are expected to be an effective drug combination regimen for PARP inhibitors in specific ovarian cancer patient groups, further expanding the applicability of PARP ( Hatchi and Livingston, 2020 ; Karakashev and Zhang, 2020 ).…”