ATM in DNA repair in cancer

doi:10.1016/j.pharmthera.2019.07.002

Pharmacology & Therapeutics

Volume 203, November 2019, 107391

https://doi.org/10.1016/j.pharmthera.2019.07.002 Get rights and content

Abstract

Alterations in DNA damage response (DDR) pathways are hallmarks of cancer. Incorrect repair of DNA lesions often leads to genomic instability. Ataxia telangiectasia mutated (ATM), a core component of the DNA repair system, is activated to enhance the homologous recombination (HR) repair pathway upon DNA double-strand breaks. Although ATM signaling has been widely studied in different types of cancer, its research is still lacking compared with other DDR-involved molecules such as PARP and ATR. There is still a vast research opportunity for the development of ATM inhibitors as anticancer agents. Here, we focus on the recent findings of ATM signaling in DNA repair of cancer. Previous studies have identified several partners of ATM, some of which promote ATM signaling, while others have the opposite effect. ATM inhibitors, including KU-55933, KU-60019, KU-59403, CP-466722, AZ31, AZ32, AZD0156, and AZD1390, have been evaluated for their antitumor effects. It has been revealed that ATM inhibition increases a cancer cell's sensitivity to radiotherapy. Moreover, the combination with PARP or ATR inhibitors has synergistic lethality in some cancers. Of note, among these ATM inhibitors, AZD0156 and AZD1390 achieve potent and highly selective ATM kinase inhibition and have an excellent ability to penetrate the blood-brain barrier. Currently, AZD0156 and AZD1390 are under investigation in phase I clinical trials. Taken together, targeting ATM may be a promising strategy for cancer treatment. Hence, further development of ATM inhibitors is urgently needed in cancer research.

Section snippets

Introduction: an overview of the DNA repair signaling network

Numerous DNA damage events occur each day in the human body by exposure to various conditions (Jackson & Bartek, 2009). These DNA lesions include simple base modifications, base mismatches, bulky DNA adducts, inter-strand and intra-strand crosslinks, protein-DNA crosslinks, DNA single-strand break (SSB) and double-strand break (DSB) (Roos, Thomas, & Kaina, 2016). When normal cells are subjected to stress that induces DNA damage, they can repair the damage through intact DNA repair pathways

ATM signaling pathways in DNA repair

Ataxia telangiectasia is an inherited recessive disease. Patients with ataxia telangiectasia exhibit multiple clinical manifestations such as cerebellar degeneration, immunodeficiency, susceptibility to malignancies, increased radiosensitivity, and metabolic diseases (Amirifar, Ranjouri, Yazdani, Abolhassani, & Aghamohammadi, 2019). Ataxia telangiectasia mutated, named ATM, belongs to the phosphatidylinositol 3-kinase-related kinase family. It has multiple functions in cancer development such

ATM alterations in cancers

Cytotoxic chemotherapeutic agents induce DNA damage in cancer cells that engage numerous factors to repair the lesions for survival (Hosoya & Miyagawa, 2014; Matt & Hofmann, 2016). Activation of ATM signaling is one of the barriers to chemotherapeutic activity and radiation resistance (Matt & Hofmann, 2016). Currently, several transcription factors have been identified to facilitate ATM activation in response to chemotherapeutic agents (Palmieri et al., 2011). To improve a patients' response to

ATM inhibitors

The antitumor effects of various kinds of ATM inhibitors have been studied in both human cancer cells and mouse models (Weber & Ryan, 2015). In this review, we outline the recent research advances in the effects of these ATM inhibitors on DNA repair pathways, including KU-55933, KU-60019, KU-59403, CP-466722, AZ31, AZ32, AZD0156, and AZD1390 (Table 1).

Clinical trials of ATM inhibitors

Among the diverse DDR-targeting agents, research on PARP inhibitors is the most advanced (Pilie et al., 2019; Sonnenblick, de Azambuja, Azim Jr., & Piccart, 2015). Olaparib and rucaparib are approved by the Food and Drug Administration for the treatment of advanced stage ovarian and breast cancers with BRCA1/2 mutation after chemotherapy (Pilie et al., 2019). In addition, there are hundreds of ongoing clinical trials evaluating PARP inhibitors.

Compared with PARP inhibitors, clinical development

Conclusions and future directions

In whole DDR networks, ATM not only plays a critical role in DNA damage repair, but also controls cell cycle progression, apoptosis, chromatin remodeling, and transcriptional regulation (O'Connor, 2015; Weber & Ryan, 2015). Because PARP inhibitors have been approved for patients with breast and ovarian cancers, hundreds of preclinical and clinical trials are being performed to evaluate DDR-targeted agents for various cancer types. Several ATM cofactors have been identified, including the MRN

Declarations of Competing Interest

D-Y Oh is a consultant and advisory board member of AstraZeneca, Novartis, Genentech, Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, and Zymework. D-Y Oh has received research grants from AstraZeneca, Novartis, Array, Eli Lilly, and Green Cross. There is no conflict of interest to declare by MH Jin.

Acknowledgments

This study was supported by a grant from The SNUH Research Fund (03-2017-0100).

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Ataxia Telangiectasia (AT) is a genetic disorder characterized by compromised DNA repair, cerebellar degeneration, and immune dysfunction. Understanding the molecular mechanisms driving AT pathology is crucial for developing targeted therapies.
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Cancer stem cells (CSCs), as parts of tumor initiation cells, play a crucial role to tumorigenesis, development and recurrence. However, the complicated mechanisms of CSCs to adapt to tumor microenvironment and its stemness maintenance remains unclear. Here, we show that oxidized ATM, a hypoxia-activated cytoplasm ATM, acts a novel function to maintain CSC stemness in triple-negative breast cancer cells (BCSCs) via regulating histone H4 acetylation. Mechanistically, oxidized ATM phosphorylates TRIM21 (a E3 ubiquitin ligase) serine 80 and serine 469. Serine 80 phosphorylation of TRIM21 is essential for the ubiquitination activity of TRIM21. TRIM21 binds with SIRT1 (one of deacetylase), resulting in ubiquitylation-mediated degradation of SIRT1. The reduced SIRT1 leads to increase of histone H4 acetylation, thus facilitating CSC-related gene expression. Clinical data verify that high level of ATM in breast tumors is positively correlated with malignant grade, and is closely related with low SIRT1, high p-TRIM21, and high CD44 expression. In conclusion, our study provides a novel mechanism by which oxidized ATM governing BCSCs stemness and reveals an important link among oxidized ATM, histone acetylation, and BCSCs maintenance.
Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer
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Gastric cancer (GC)is the third leading cause of cancer-related deaths in China and immunotherapy emerging as a revolutionary treatment for GC recently. Tumor mutational burden (TMB) is a predictive biomarker of immunotherapy in multiple cancers. However, the prognostic significance and subtype of TMB in GC is not fully understood.
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ATM in DNA repair in cancer

Abstract

Section snippets

Introduction: an overview of the DNA repair signaling network

ATM signaling pathways in DNA repair

ATM alterations in cancers

ATM inhibitors

Clinical trials of ATM inhibitors

Conclusions and future directions

Declarations of Competing Interest

Acknowledgments

Free Radical Biology & Medicine

Cell Reports

Molecular Cell

Oral Oncology

Cell Reports

Cell

Cancer Treatment Reviews

Molecular Oncology

Trends in Cell Biology

Trends in Immunology

Pharmacology & Therapeutics

DNA Repair (Amst)

Cell Reports

Cancer Cell

Cell

The Journal of Biological Chemistry

Experimental Cell Research

DNA Repair (Amst)

Cancer Letters

Current Opinion in Genetics & Development

Molecular Cell

Cell Reports

Pharmacology & Therapeutics

DNA Repair (Amst)

Ataxia-telangiectasia: A review of clinical features and molecular pathology

Pediatric Allergy and Immunology

PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer

Oncoimmunology

ATM and ATR signaling at a glance

Journal of Cell Science

Susceptibility of ATM-deficient pancreatic cancer cells to radiation

Cell Cycle

Structures of closed and open conformations of dimeric human ATM

Science Advances

STAT3 modulates the DNA damage response pathway

International Journal of Experimental Pathology

Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer

Molecular Cancer Therapeutics

At the intersection of DNA damage and immune responses

Nature Reviews. Immunology

Promoter Hypermethylation of the ATM gene as a novel biomarker for breast cancer

Asian Pacific Journal of Cancer Prevention

RPA and RAD51: Fork reversal, fork protection, and genome stability

Nature Structural & Molecular Biology

ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation

Clinical Cancer Research

Regulation of DNA repair throughout the cell cycle

Nature Reviews Molecular Cell Biology

The clinical significance of PD-L1 in advanced gastric cancer is dependent on ARID1A mutations and ATM expression

Oncoimmunology

Non-homologous DNA end joining and alternative pathways to double-strand break repair

Nature Reviews Molecular Cell Biology

Homology-directed repair and the role of BRCA1, BRCA2, and related proteins in genome integrity and Cancer

Annual Review Cancer Biology

INPP4B overexpression suppresses migration, invasion and angiogenesis of human prostate cancer cells

Clinical and Experimental Pharmacology & Physiology

ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion

Elife

ATM mutations in Cancer: Therapeutic implications

Molecular Cancer Therapeutics

ATM signalling and cancer

Oncogene

DNA repair dysregulation from cancer driver to therapeutic target

Nature Reviews Cancer

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models

Science Advances

ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition

Journal of Experimental & Clinical Cancer Research

Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion