Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma

Jian-Fang Ning; Monica Stanciu; Melissa R. Humphrey; Joshua Gorham; Hiroko Wakimoto; Reiko Nishihara; Jacqueline Lees; Lee Zou; Robert L. Martuza; Hiroaki Wakimoto; Samuel D. Rabkin

doi:10.1038/s41467-019-10993-5

Nature Communications (Jul 2019)

Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma

Jian-Fang Ning,
Monica Stanciu,
Melissa R. Humphrey,
Joshua Gorham,
Hiroko Wakimoto,
Reiko Nishihara,
Jacqueline Lees,
Lee Zou,
Robert L. Martuza,
Hiroaki Wakimoto,
Samuel D. Rabkin

Affiliations

Jian-Fang Ning: Molecular Neurosurgery Laboratory and the Brain Tumor Research Center and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School
Monica Stanciu: The David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology
Melissa R. Humphrey: Molecular Neurosurgery Laboratory and the Brain Tumor Research Center and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School
Joshua Gorham: Department of Genetics, Harvard Medical School
Hiroko Wakimoto: Department of Genetics, Harvard Medical School
Reiko Nishihara: Department of Pathology, Brigham’s and Women’s Hospital and Harvard Medical School
Jacqueline Lees: The David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology
Lee Zou: Department of Pathology, Massachusetts General Hospital and Harvard Medical School
Robert L. Martuza: Molecular Neurosurgery Laboratory and the Brain Tumor Research Center and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School
Hiroaki Wakimoto: Molecular Neurosurgery Laboratory and the Brain Tumor Research Center and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School
Samuel D. Rabkin: Molecular Neurosurgery Laboratory and the Brain Tumor Research Center and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School

DOI: https://doi.org/10.1038/s41467-019-10993-5
Journal volume & issue: Vol. 10, no. 1
pp. 1 – 18

Abstract

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PARP inhibitors are mainly used to treat BRCA1/2 mutated cancers. Here, the authors show that MYC amplified glioblastomas are sensitive to PARP inhibition due to CDK18 repression, which impairs ATR regulated homologous recombination repair, and that ATR inhibition sensitises glioblastomas to PARP inhibition.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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