The novel ATM inhibitor (AZ31) enhances antitumor activity in patient derived xenografts that are resistant to irinotecan monotherapy

Greene, Justin M.; Nguyen, Anna; Bagby, Stacey M.; Jones, Gemma N.; Tai, Wai Meng David; Quackenbush, Kevin S.; Schreiber, Anna; Messersmith, Wells A.; Devaraj, Kalpana; Blatchford, Patrick J.; Eckhardt, S. Gail; Cadogan, Elaine; Hughes, Gareth; Smith, Aaron; Pitts, Todd M.; Arcaroli, John J.

doi:10.18632/oncotarget.22920

Cited by 19 publications

(30 citation statements)

References 23 publications

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“…This compound was shown to inhibit downstream ATM phosphorylation after radiation, and it also enhanced responses to the topoisomerase inhibitors etoposide, camptothecins, and doxorubicin (73). A similar sensitization to topoisomerase inhibitors was later demonstrated with the ATM inhibitor AZ31, which was shown to increase the efficacy of irinotecan in resistant tumors in PDX models (74). KU60019 is another compound that was introduced in 2009 as an improved analogue of KU55933 (75), and early work demonstrated that KU60019 is a potent radiosensitizer (75).…”

Section: Atm Inhibitorsmentioning

confidence: 72%

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

Armstrong

Schultz

Azimi-Sadjadi

et al. 2019

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with very few therapeutic options to treat advanced or metastatic disease. The utilization of genomic sequencing has identified therapeutically relevant alterations in approximately 25% of PDAC patients, most notably in the DNA damage response and repair (DDR) genes, rendering cancer cells more sensitive to DNA-damaging agents and to DNA damage response inhibitors, such as PARP inhibitors. ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2% to 18% of PDACs and germline mutations identified in 1% to 34% of PDACs. ATM plays a complex role as a cell-cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability. The disruption of ATM signaling leads to downstream reliance on ATR and CHK1, among other DNA-repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in ATM-mutated PDACs. In this review, we detail the function of ATM, review the current data on ATM deficiency in PDAC, examine the therapeutic implications of ATM alterations, and explore the current clinical trials surrounding the ATM pathway.

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Section: Atm Inhibitorsmentioning

confidence: 72%

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

Armstrong

Schultz

Azimi-Sadjadi

et al. 2019

Molecular Cancer Therapeutics

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“…We anticipate that AZD0156 will also potentiate the effects of other clinically relevant DSB-inducing agents such as topoisomerase inhibitors (e.g., irinotecan and topotecan; refs. 21,38).…”

Section: Discussionmentioning

confidence: 99%

Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically

Riches

Trinidad

Hughes

et al. 2020

Molecular Cancer Therapeutics

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117

107

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AZD0156 is a potent and selective, bioavailable inhibitor of ataxia-telangiectasia mutated (ATM) protein, a signaling kinase involved in the DNA damage response. We present preclinical data demonstrating abrogation of irradiation-induced ATM signaling by low doses of AZD0156, as measured by phosphorylation of ATM substrates. AZD0156 is a strong radiosensitizer in vitro, and using a lung xenograft model, we show that systemic delivery of AZD0156 enhances the tumor growth inhibitory effects of radiation treatment in vivo. Because ATM deficiency contributes to PARP inhibitor sensitivity, preclinically, we evaluated the effect of combining AZD0156 with the PARP inhibitor olaparib. Using ATM isogenic FaDu cells, we demonstrate that AZD0156 impedes the repair of olaparib-induced DNA damage, resulting in elevated DNA double-strand break signaling, cellcycle arrest, and apoptosis. Preclinically, AZD0156 potentiated the effects of olaparib across a panel of lung, gastric, and breast cancer cell lines in vitro, and improved the efficacy of olaparib in two patient-derived triple-negative breast cancer xenograft models. AZD0156 is currently being evaluated in phase I studies (NCT02588105).

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“…5A, right panel). To directly assess the importance of ATM kinase activity (66,69,70) in HSATII RNA induction the effect of Ku-55933 or AZ31, ATM kinase inhibitors (71,72), were tested. Neither drug compromised the viability of ARPE-19 cells when tested at concentrations up to 50 µM (Fig.…”

Section: Zeocin Treatment Substantially Mimics the Transcriptional Efmentioning

confidence: 99%

“…5B, left panel). However, because we noticed morphological changes in treated cells at the highest dose (50 µM), we used Ku-55933 and AZ31 at 20 µM, which is in the range of concentrations at which these drugs are typically used (71)(72)(73). Cells were pretreated with Ku-55933 or AZ31 for 2 h before being treated with zeocin (100 µg/mL).…”

Section: Zeocin Treatment Substantially Mimics the Transcriptional Efmentioning

confidence: 99%

HSATII RNA is inducedviaa non-canonical ATM-regulated DNA-damage response pathway and facilitates tumor cell proliferation and movement

Nogalski

Shenk

2020

Preprint

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Recently, we documented that human cytomegalovirus (HCMV) and herpes simplex virus (HSV) infections lead to a robust induction of HSATII RNA, among other satellite repeat transcripts. HSATII RNA positively affects viral gene expression, DNA accumulation and yield, as well as has a broad influence on host cell biology. Our report also provided evidence that cooperation between at least two HCMV immediate-early proteins (IE1, IE2) is necessary for the robust induction of HSATII RNA expression. However, cellular processes contributing to the virus-induced HSATII RNA were still unknown. Here, we report that the strength with which HSATII RNA affects virus replication cycle is cell-type specific with retinal pigment epithelial cells being markedly more sensitive to levels of HSATII RNA than fibroblasts. We demonstrate that the HCMV IE1 and IE2 proteins regulate HSATII expression via the E2F3a transcription factor. Moreover, treatment of cells with DNA damaging agents also induced HSATII expression, and we determined that a rerouted DNA damage response (DDR) pathway, based on kinase independent ATM regulation, plays a central role in the expression of HSATII in HCMV-infected cells. Importantly, we discovered that, depending on the HSATII RNA levels, breast cancer cells showed differential sensitivity to DNA damaging drugs with enhanced cell migration seen in less metastatic cells. Additionally, we demonstrate that highly motile and proliferative phenotype of metastatic breast cancer cells can be effectively inhibited by knocking down HSATII RNA. Together, our investigation provides the molecular mechanism that links a high expression of HSATII RNA to the E2F3a-initiated induction of DDR, centered on kinase-independent functions of ATM, and to processes critical for efficient viral infection, cancer cell migration and proliferation.

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The novel ATM inhibitor (AZ31) enhances antitumor activity in patient derived xenografts that are resistant to irinotecan monotherapy

Cited by 19 publications

References 23 publications

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically

HSATII RNA is inducedviaa non-canonical ATM-regulated DNA-damage response pathway and facilitates tumor cell proliferation and movement

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