Targeting Mutant PPM1D Sensitizes Diffuse Intrinsic Pontine Glioma Cells to the PARP Inhibitor Olaparib.

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an invariably fatal brain tumor occurring predominantly in children. Up to 90% of pediatric DIPGs harbor a somatic heterozygous mutation resulting in the replacement of lysine 27 with methionine (K27M) in genes encoding histone H3.3 (H3F3A, 65%) or H3.1 (HIST1H3B, 25%). Several studies have also identified recurrent truncating mutations in the gene encoding protein phosphatase 1D, PPM1D, in 9%-23% of DIPGs. Here, we sought to investigate the therapeutic potential of targeting PPM1D, alone or in combination with inhibitors targeting specific components of DNA damage response pathways in patient-derived DIPG cell lines. We found that GSK2830371, an allosteric PPM1D inhibitor, suppressed the proliferation of PPM1D-mutant, but not PPM1D wild-type DIPG cells. We further observed that PPM1D inhibition sensitized PPM1D-mutant DIPG cells to PARP inhibitor (PARPi) treatment. Mechanistically, combined PPM1D and PARP inhibition show synergistic effects on suppressing a p53-dependent RAD51 expression and the formation of RAD51 nuclear foci, possibly leading to impaired homologous recombination (HR)-mediated DNA repair in PPM1D-mutant DIPG cells. Collectively, our findings reveal the potential role of the PPM1D-p53 signaling axis in the regulation of HR-mediated DNA repair and provide preclinical evidence demonstrating that combined inhibition of PPM1D and PARP1/2 may be a promising therapeutic combination for targeting PPM1D-mutant DIPG tumors. IMPLICATIONS: The findings support the use of PARPi in combination with PPM1D inhibition against PPM1D-mutant DIPGs.