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

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 BRCA-proficient 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 BRCA1/2-proficient 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.