Inhibition of mutant PPM1D enhances DNA damage response and growth suppressive effects of ionizing radiation in diffuse intrinsic pontine glioma.

ABSTRACT:

Background

Children with diffuse intrinsic pontine glioma (DIPG) succumb to disease within 2 years of diagnosis despite treatment with ionizing radiation (IR) and/or chemotherapy. Our aim was to determine the role of protein phosphatase, magnesium-dependent 1, delta (PPM1D) mutation, present in up to 25% of cases, in DIPG pathogenesis and treatment.

Methods

Using genetic and pharmacologic approaches, we assayed effects of PPM1D mutation on DIPG growth and murine survival. We assayed effects of targeting mutated PPM1D alone or with IR on signaling, cell cycle, proliferation, and apoptosis in patient-derived DIPG cells in vitro, in organotypic brain slices, and in vivo.

Results

PPM1D-mutated DIPG cell lines exhibited increased proliferation in vitro and in vivo, conferr

SUBMITTER: Akamandisa MP 

PROVIDER: S-EPMC6556861 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature