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

inhibitors 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 via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and Pduanyu37i resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred Pduanyu37i sensitivity, with ATR inhibitors synergizing with or sensitizing GSCs. ATR inhibitor VE822 combined with Pduanyu37i extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and Pduanyu37 is an effective strategy for GBM, even for low-Myc GSCs that do not respond to Pduanyu37i alone, and potentially other tumors.

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