Abstract Inhibition of the p53 pathway is a common early event in pediatric high-grade glioma (pHGG) evolution but approximately 50% of all pHGGs retain a wild-type TP531, instead inhibiting the pathway through activating alterations in negative regulators of p53, like activating truncations of the PPM1D phosphatase, or amplifications of MDM2 or MDM4. These alterations produce incomplete, partial inactivation of p53, rendering these tumors susceptible to therapies designed to restore p53 function, such as PPM1D inhibition. Such ‘p53-reactivating’ therapies have shown pre-clinical promise in various p53-wild type cancers. PPM1D inhibition has shown potential efficacy in preclinical models of multiple diseases2-6, including pHGGs, clonal hematopoiesis of indeterminate potential, and endometrial cancer, leading to efforts current efforts to develop small molecules to therapeutically target PPM1D. However, p53-reactivating therapies focused on inhibiting MDM2/MDM4 have been hampered by the rapid emergence of secondary resistance7-9. We anticipate that such resistance may also occur in the setting of PPM1D inhibition and hypothesized that pre-emptively targeting common mechanisms of resistance may increase the therapeutic efficacy of PPM1D inhibition. Using genome-wide CRISPR-activating screens, we identified PPM1G, a PP2C phosphatase family member, which, when overexpressed was sufficient to rescue pHGG cells from PPM1D inhibition. We performed functional profiling to demonstrate that PPM1G has paralogous function to PPM1D, and that inhibition of PPM1G increases the sensitivity of pHGG cells to PPM1D inhibition. These results uncover a new function of PPM1G in mediating the DNA damage response, and provide a potential therapeutic approach to increase the efficacy of PPM1D-inhibitors in p53-wild type pHGGs. 1. Dubois, F. P. B. et al. Structural variants shape driver combinations and outcomes in pediatric high-grade glioma. Nat Cancer 1–18 (2022) doi:10.1038/s43018-022-00403-z. 2. Khadka, P. et al. PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation. Nat Commun 13, 604 (2022) 3. Miller, P. G. et al. Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state. Nat. Commun. 13, 3778 (2022) 4. Jiang, W. et al. Identification of Small Molecule Inhibitors of PPM1D Using a Novel Drug Discovery Platform. bioRxiv 2024.05.20.595001 (2024) doi:10.1101/2024.05.20.595001 5. Rayter, S. et al. A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D. Oncogene 27, 1036–1044 (2008) 6. Ogasawara, S. et al. Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation. Bioorganic & medicinal chemistry 23, 6246–6249 (2015). 7. Rendo, V. et al. A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma. Sci. Transl. Med. 17, eadn6274 (2025) 8. Jones, R. J., Bjorklund, C. C., Baladandayuthapani, V., Kuhn, D. J. & Orlowski, R. Z. Drug Resistance to Inhibitors of the Human Double Minute-2 E3 Ligase Is Mediated by Point Mutations of p53, but Can Be Overcome with the p53 Targeting Agent RITA. Mol. Cancer Ther. 11, 2243–2253 (2012). 9. Aziz, M. H., Shen, H. & Maki, C. G. Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3. Oncogene 30, 4678–4686 (2011).
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