ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma

Daniel J. Laverty, Shiv K. Gupta, Gary A. Bradshaw, Alexander S. Hunter, Brett L. Carlson, Nery Matias Calmo, Jiajia Chen, Shulan Tian, Jann N. Sarkaria and Zachary D. Nagel ()
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Daniel J. Laverty: Harvard T.H. Chan School of Public Health
Shiv K. Gupta: Mayo Clinic
Gary A. Bradshaw: Harvard Medical School
Alexander S. Hunter: Harvard Medical School
Brett L. Carlson: Mayo Clinic
Nery Matias Calmo: Harvard T.H. Chan School of Public Health
Jiajia Chen: Mayo Clinic
Shulan Tian: Mayo Clinic
Jann N. Sarkaria: Mayo Clinic
Zachary D. Nagel: Harvard T.H. Chan School of Public Health

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We screen clinically relevant small molecules for DSBR inhibition with the aim of identifying improved GBM combination therapy regimens. We identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor that suppresses radiation-induced phosphorylation of DSBR proteins, blocks DSB end resection, and enhances the cytotoxic effects of TMZ in treatment-naïve and treatment-resistant GBMs with TP53 mutation. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.

Date: 2024
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DOI: 10.1038/s41467-024-49316-8

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