Reference Detail

Ref Type

Journal Article

PMID

(34118569)

Authors

Garbarino J, Eckroate J, Sundaram RK, Jensen RB, Bindra RS

Title

Loss of ATRX confers DNA repair defects and PARP inhibitor sensitivity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Translational oncology	14	9	2021 Jun 09	101147	Transl Oncol

URL

Abstract Text

Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) is mutated frequently in gliomas and represents a potential target for cancer therapies. ATRX is known to function as a histone chaperone that helps incorporate histone variant, H3.3, into the genome. Studies have implicated ATRX in key DNA damage response (DDR) pathways but a distinct role in DNA repair has yet to be fully elucidated. To further investigate the function of ATRX in the DDR, we created isogenic wild-type (WT) and ATRX knockout (KO) model cell lines using CRISPR-based gene targeting. These studies revealed that loss of ATRX confers sensitivity to poly(ADP)-ribose polymerase (PARP) inhibitors, which was linked to an increase in replication stress, as detected by increased activation of the ataxia telangiectasia and Rad3-related (ATR) signaling axis. ATRX mutations frequently co-occur with mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2), and the latter mutations also induce HR defects and PARP inhibitor sensitivity. We found that the magnitude of PARP inhibitor sensitivity was equal in the context of each mutation alone, although no further sensitization was observed in combination, suggesting an epistatic interaction. Finally, we observed enhanced synergistic tumor cell killing in ATRX KO cells with ATR and PARP inhibition, which is commonly seen in HR-defective cells. Taken together, these data reveal that ATRX may be used as a molecular marker for DDR defects and PARP inhibitor sensitivity, independent of IDH1/2 mutations. These data highlight the important role of common glioma-associated mutations in the regulation of DDR, and novel avenues for molecularly guided therapeutic intervention.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ATRX loss IDH1 R132H	high grade glioma	predicted - sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment inhibited viability of immortalized astrocytes expressing IDH1 R132H with loss of ATRX in culture (PMID: 34118569).	34118569
IDH1 R132H	high grade glioma	sensitive	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, Talzenna (talazoparib) treatment inhibited viability of immortalized astrocytes expressing IDH1 R132H in culture (PMID: 34118569).	34118569
ATRX loss	high grade glioma	predicted - sensitive	Ceralasertib + Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Ceralasertib (AZD6738) and Lynparza (olaparib) synergized to inhibit viability of immortalized astrocytes with loss of ATRX in culture (PMID: 34118569).	34118569
ATRX loss	high grade glioma	predicted - sensitive	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, Talzenna (talazoparib) treatment inhibited viability of immortalized astrocytes with loss of ATRX in culture (PMID: 34118569).	34118569
ATRX loss IDH1 R132H	high grade glioma	predicted - sensitive	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, Talzenna (talazoparib) treatment inhibited viability of immortalized astrocytes expressing IDH1 R132H with loss of ATRX in culture (PMID: 34118569).	34118569
IDH1 R132H	high grade glioma	predicted - sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment inhibited viability of a glioma cell line expressing IDH1 R132H in culture (PMID: 34118569).	34118569
ATRX loss	high grade glioma	predicted - sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment inhibited viability of immortalized astrocytes with loss of ATRX in culture (PMID: 34118569).	34118569