Abstract
Abstract p53 pathway reactivation through pharmacologic inhibition of negative regulators was identified as a promising therapeutic strategy for TP53 wild-type (WT) high-grade gliomas, including Diffuse Midline Gliomas (DMGs). Despite widespread theoretical promise, the therapeutic efficacy of MDM2 inhibitors and PPM1D inhibitors as single agents have each been limited by issues, including sub-lethal effects on cancer cells and innate or emerging resistance leading to tumor progression. We carried out a genome-scale CRISPR activating (CRISPRa) screen to identify genes that, when overexpressed, confer resistance to p53 reactivation therapies. NAD(P)H quinone dehydrogenase 1 (NQO1) emerged as a top hit and was confirmed through secondary CRISPRa screens and low-throughput validations as driving a resistance phenotype in TP53 WT DMGs. Our subsequent work has aimed to elucidate the mechanisms through which NQO1 mediates the effects of p53 reactivation therapies, and assess the feasibility and impact of exploiting NQO1 in combination therapies towards a cure.
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