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 () and Samuel D. Rabkin ()
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Jian-Fang Ning: Massachusetts General Hospital and Harvard Medical School
Monica Stanciu: Massachusetts Institute of Technology
Melissa R. Humphrey: Massachusetts General Hospital and Harvard Medical School
Joshua Gorham: Harvard Medical School
Hiroko Wakimoto: Harvard Medical School
Reiko Nishihara: Brigham’s and Women’s Hospital and Harvard Medical School
Jacqueline Lees: Massachusetts Institute of Technology
Lee Zou: Massachusetts General Hospital and Harvard Medical School
Robert L. Martuza: Massachusetts General Hospital and Harvard Medical School
Hiroaki Wakimoto: Massachusetts General Hospital and Harvard Medical School
Samuel D. Rabkin: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.

Date: 2019
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DOI: 10.1038/s41467-019-10993-5

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