Journal of Clinical & Experimental Pharmacology

Abstract

PPM1D Truncation-associated Overexpression of the Stress-related Protein NQO1 Confers Sensitivity to the Bioactivatable Drug IB-DNQ in Diffuse Intrinsic Pontine Glioma

Maxime Janin*

Diffuse Intrinsic Pontine Glioma (DIPG) is a very aggressive brainstem tumor with a dismal prognosis and a lack of effective treatments. This study identifies the differential overexpression of the stress-related protein NAD(P) H Quinone Dehydrogenase 1 (NQO1) in some patient-derived DIPG cell lines and tumors. Given the critical role of NQO1 in cellular stress response, the objective was to clarify the mechanisms underlying its regulation in DIPG, while also exploring the therapeutic potential of the NQO1-bioactivatable drug Isobutyl-deoxynyboquinone (IB-DNQ). Interestingly, the study of the mutational profiles of the cell lines indicated that truncation of PPM1D correlated with NQO1 overexpression. From a functional perspective, cellular models were utilized to resolve that PPM1D phosphatase regulates NQO1 expression through the dephosphorylation of Mouse Double Minute 2 homolog (MDM2) at serine 395, resulting in the increased rate of translation of NQO1. From a therapeutic perspective, IB-DNQ treatment showed an NQO1-dependent growth inhibition sensitivity in vitro and extended survival in an in vivo DIPG model. These results reveal a new regulation of NQO1 at the protein level in PPM1D- mutated DIPGs indicating a potential therapeutic approach.

Published Date: 2024-10-28; Received Date: 2024-09-26