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ATM Inhibition Exploits Checkpoint Defects and ATM-Dependent Double Strand Break Repair in TP53-Mutant Glioblastoma

ABSTRACT: Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a novel method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). This approach revealed enhanced MMEJ and HR in glioblastoma (GBM) xenograft models with acquired temozolomide (TMZ) resistance. Knockdown of proteins in either pathway enhanced killing by TMZ, and a targeted screen identified pharmacological-grade dual HR/MMEJ inhibitors, including AZD1390, an ATM kinase inhibitor. AZD1390 suppressed DSB end resection, blocked phosphorylation of end protection proteins in response to DNA damage, and potentiated TMZ in treatment-naïve and treatment-resistant models. TP53-mutant GBMs were most susceptible to AZD1390 in combination with DNA-damaging agents due to elevated ATM-dependent HR/MMEJ, preferential activation of these pathways in response to DNA damage, and a defective G2/M checkpoint, which caused these GBMs to enter mitosis despite unrepaired DNA damage, leading to cell death via apoptosis. This report establishes 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Glioblastoma

SUBMITTER: Gary Bradshaw

LAB HEAD: Zachary D. Nagel

PROVIDER: PXD047837 | Pride | 2024-03-08

REPOSITORIES: Pride

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			Action	DRS
	606002_ZN_phospho_9plex_Fr1_14811_psc_20ppm.mzIdentML	Mzid
	606004_ZN_phospho_9plex_Fr2_14812_psc_20ppm.mzIdentML	Mzid
	606006_ZN_phospho_9plex_Fr3_14813_psc_20ppm.mzIdentML	Mzid
	606008_ZN_phospho_9plex_Fr4_14814_psc_20ppm.mzIdentML	Mzid
	606010_ZN_phospho_9plex_Fr5_14815_psc_20ppm.mzIdentML	Mzid

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Project description:Introduction: The EORTC22033-26033 clinical trial investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared to radiotherapy (RT) in low grade glioma patients. In this study we performed gene expression profiling on tissues from this trial in order to identify markers associated with progression free survival and treatment response in this well-defined cohort of patients. Methods: Gene expression profiling, performed on 195 samples, was used to assign tumors to one of six intrinsic glioma subtypes (IGS; molecularly similar tumors predefined by unsupervised gene expression analysis) and to extract the cellular composition of immune infiltrates. DNA copy number changes were determined on samples assigned to IGS-16. Results: We confirm that IGS-subtypes are prognostic in EORTC22033-26033 clinical trial samples. Specific genetic changes segregate in distinct IGS subtypes: most samples assigned to IGS-9 have IDH-mutations combined with 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations with intact 1p19q chromosomal arms and samples assigned to other intrinsic subtypes often are IDH-wildtype and 1p19q intact. A trend towards benefit from RT compared to TMZ was observed for samples assigned to IGS-9 (HR for TMZ is 1.90, 95% CI [0.95, 3.80], P=0.065), but not for samples assigned to IGS-17 (HR for TMZ vs RT is 0.87, 95% CI[0.50, 1.51], P=0.62). We did not identify genes significantly associated with progression free survival (PFS) within intrinsic subtypes, though follow-up time is limited. We also show that LGGs and GBMs differ in their immune-infiltrate with LGGs having higher suppressor and lower effector cell populations compared to GBMs. This suggests that LGGs are less amenable to checkpoint inhibitor type immune therapies than GBMs. Gene expression analysis and copy number analysis also identified one patient with a pilocytic astrocytoma (PA). Conclusion: Intrinsic glioma subtypes are prognostic for PFS in EORTC22033-26033 clinical trial samples.

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ATM Inhibition Exploits Checkpoint Defects and ATM-Dependent Double Strand Break Repair in TP53-Mutant Glioblastoma

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