PPM1D truncation-associated overexpression of the stress-related protein NQO1 confers sensitivity to the bioactivatable drug IB-DNQ in diffuse intrinsic pontine glioma
Janin, M.
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Diffuse intrinsic pontine glioma (DIPG) is a very aggressive brainstem tumor with poor survival and a lack of effective treatments. In this study, I observed the differential overexpression of the stress-related protein NAD(P)H Quinone Dehydrogenase 1 (NQO1) in some patient-derived DIPG cell lines and tumors. I sought to understand how this protein is regulated in DIPG and to investigate 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 standpoint, cellular models were utilized to unravel the link between PPM1D phosphatase and NQO1 expression in DIPG by dephosphorylating MDM2 serine 395, leading to NQO1 protein stabilization. From a therapeutic perspective, IB-DNQ treatment showed an NQO1-dependent growth inhibition sensitivity in vitro and induced an extended survival in vivo. Overall, my results reveal a new regulation of NQO1 at the protein level in PPM1D-mutated DIPG indicating a promising therapeutic approach.
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