AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells

Min, Ahrum; Im, Seock Ah; Jang, Hyemin; Kim, Seongyeong; Lee, Miso; Kim, Debora Keunyoung; Yang, Yaewon; Kim, Hee Jun; Lee, Kyung Hun; Kim, Jin Won; Kim, Tae Yong; Oh, Do Youn; Brown, Jeff; Lau, Alan; O’Connor, Mark J.; Bang, Yung Jue

doi:10.1158/1535-7163.mct-16-0378

Cited by 121 publications

(73 citation statements)

References 41 publications

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“…The AZD6738 IC 50 in the most sensitive cell lines were lower than those recently reported in the chronic lymphocytic leukemia cell lines (29) and gastric cancer cells with ATM or TP53 dysfunction (37), corroborating the evidence that at least in this experimental setting the highest sensitivity to AZD6738 is not strictly and exclusively associated with ATM mutational status/expression. Hocke and colleagues (39) identified POLD1 and other DNA repair genes, other than ATM, as synthetically lethal with ATR.…”

Section: Discussionsupporting

confidence: 84%

DNA Damage Response Inhibitor Combinations Exert Synergistic Antitumor Activity in Aggressive B-Cell Lymphomas

Restelli

Lupi

Chilà

et al. 2019

Molecular Cancer Therapeutics

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The DNA damage response (DDR) kinases ATR, Chk1, and Wee1 play vital roles in the response to replication stress and in maintaining cancer genomic stability. Inhibitors of these kinases are currently under clinical investigation. Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are aggressive lymphomas whose clinical outcome is still largely unsatisfactory. These cell lymphoma subtypes are highly dependent on both Chk1 and Wee1 for survival. We investigated the activity of the ATR inhibitor AZD6738 as single agent and in combination with either Chk1 (AZD6738) or Wee1 (AZD1775) inhibitors in several preclinical models of MCL and DLBCL. This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, and validation experiments on in vivo models. Cellular and molecular mechanisms of the observed synergistic effect as well as pharmacodynamic analysis of in vivo samples were studied. AZD6738 exerted a strong synergistic cytotoxic effect in combination with both AZD7762 and AZD1775 in the 2 lymphoma subtypes regardless of their TP53, MYC, and ATM mutational status. These DDR inhibitor combinations, similarly to the Chk1/Wee1 inhibitor combination, caused a marked S-phase delay, with an increase in cyclin-dependent kinases (CDK) activity, increased DNA damage, and decreases in Wee1, MYC, and RRM2 protein levels. The synergistic in vitro activity translated to striking in vivo antitumor activity. DDR-DDR inhibitor combinations could potentially offer promising novel therapeutic strategies for patients with B-cell lymphoma.

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Section: Discussionsupporting

confidence: 84%

DNA Damage Response Inhibitor Combinations Exert Synergistic Antitumor Activity in Aggressive B-Cell Lymphomas

Restelli

Lupi

Chilà

et al. 2019

Molecular Cancer Therapeutics

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“…S9). The magnitude of this effect appeared as substantial as compared to the previously reported effects of AZD6738 against tumors with genetic deficiencies of ATM, XRCC1 or ERCC1 (35)(36)(37)(38). Similar effects were observed using Kaplan-Meier survival analysis (log-rank p = 1.0e-3 and 1.0e-4, respectively, Figure S11).…”

Section: Azd6738 Induces Dna Damage Apoptosis and Exhibits Anti-tumsupporting

confidence: 80%

Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

Henssen¹,

Reed

Jiang³

et al. 2017

Preprint

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Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory.Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have now found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma and Ewing sarcoma, express an active DNA transposase PGBD5 that can promote site-specific genomic rearrangements in human cells.Using functional genetic approaches, we found that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity-deficient mutant, was sufficient to induce hypersensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment, and underwent apoptosis in both dividing and G1 phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against the majority of neuroblastoma, medulloblastoma, Ewing sarcoma and rhabdoid tumor cells tested, while sparing non-transformed human and mouse embryonic fibroblasts in vitro.Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including significant anti-tumor activity against patientderived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.peer-reviewed)

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“…Rather, olaparib was found to induce reversible G2 arrest in ATM-deficient A549 cells [61]. Since the related protein kinase ATR plays a critical role in the G2 checkpoint [62], and given ATM-deficient cells are sensitive to ATR inhibitors [58,[63][64][65], we asked whether inhibition of ATR using VE-821 [66,67], would ablate G2 arrest and induce cell death in olaparib-treated ATM-deficient cells. This was indeed found to be the case.…”

Section: Targeting Atm-deficient Cancersmentioning

confidence: 99%

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Jette

Kumar

Radhamani

et al. 2020

Cancers

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Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.

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AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells

Cited by 121 publications

References 41 publications

DNA Damage Response Inhibitor Combinations Exert Synergistic Antitumor Activity in Aggressive B-Cell Lymphomas

DNA Damage Response Inhibitor Combinations Exert Synergistic Antitumor Activity in Aggressive B-Cell Lymphomas

Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

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