Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group

Annals of Oncology, Год журнала: 2020, Номер 31(11), С. 1491 - 1505

Опубликована: Авг. 24, 2020

Язык: Английский

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DNA damage checkpoint kinases in cancer

Expert Reviews in Molecular Medicine, Год журнала: 2020, Номер 22

Опубликована: Янв. 1, 2020

Abstract DNA damage response (DDR) pathway prevents high level endogenous and environmental being replicated passed on to the next generation of cells via an orchestrated integrated network cell cycle checkpoint signalling repair pathways. Depending type damage, where in it occurs different pathways are involved, with ATM-CHK2-p53 controlling G1 or ATR-CHK1-Wee1 S G2/M checkpoints. Loss control is common cancer through TP53, ATM mutations, Rb loss cyclin E overexpression, providing a stronger rationale for targeting S/G2 This review will focus ATM-CHK2-p53-p21 ATR-CHK1-WEE1 ongoing efforts target these patient benefit.

Язык: Английский

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ATM in DNA repair in cancer

Pharmacology & Therapeutics, Год журнала: 2019, Номер 203, С. 107391 - 107391

Опубликована: Июль 9, 2019

Язык: Английский

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Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells

Oncogene, Год журнала: 2020, Номер 39(25), С. 4869 - 4883

Опубликована: Май 23, 2020

Abstract The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA -mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity traps PARP1 on DNA at single-strand breaks, leading to replication-induced damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, response pathways mediated by ataxia-telangiectasia mutated (ATM) Rad3-related (ATR) kinases are hypothesised be important survival in PARP-inhibitor treatment. Here, we show combines synergistically with ATR-inhibitor AZD6738 (ceralasertib), vitro, selective cell death ATM-deficient cells. We observe 24 h causes cells accumulate G2-M cycle, however, co-administration releases olaparib-treated from G2 arrest. Selectively ATM -knockout cells, combined olaparib/AZD6738 induces more chromosomal aberrations achieves this lower concentrations earlier time-points than either monotherapy. Furthermore, single-agent efficacy vitro PARP inhibition throughout multiple rounds replication. demonstrate several lines combination within 1–2 divisions, suggesting could circumvent need prolonged drug exposure. Finally, vivo xenograft PDX mouse models complete loss. Collectively, these data provide a mechanistic understanding ATR models, support clinical development olaparib.

Язык: Английский

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DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities

Experimental & Molecular Medicine, Год журнала: 2022, Номер 54(10), С. 1658 - 1669

Опубликована: Окт. 7, 2022

Abstract Antitumor therapeutic strategies that fundamentally rely on the induction of DNA damage to eradicate and inhibit growth cancer cells are integral approaches therapy. Although DNA-damaging therapies advance battle with cancer, resistance, recurrence following treatment common. Thus, searching for vulnerabilities facilitate action agents by sensitizing is an active research area. Therefore, it crucial decipher detailed molecular events involved in responses (DDRs) cancer. The tumor suppressor p53 at hub DDR. Researchers have identified increasing number genes regulated transcriptional functions been shown be critical direct or indirect mediators cell fate, cycle regulation, repair. Posttranslational modifications (PTMs) primarily orchestrate activity response damage. Many molecules mediating PTMs identified. anticancer potential realized targeting these has through experiments clinical trials sensitize agents. This review briefly acknowledges complexity DDR pathways/networks. We specifically focus regulators, protein kinases, E3/E4 ubiquitin ligases their potential.

Язык: Английский

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The DNA Damage Response and Inflammation in Cancer

Cancer Discovery, Год журнала: 2023, Номер 13(7), С. 1521 - 1545

Опубликована: Апрель 7, 2023

Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting demise with unrepairable lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig-naling can also favor progression resistance therapy. Indeed, signaling cancer has been consistently linked inhibition tumor-targeting immune responses. Here, we discuss complex interactions between inflammation context oncogenesis, progression, Accumulating preclinical clinical evidence indicates that intimately connected emission immunomodulatory signals malignant cells, part a program preserve organismal homeostasis. DDR-driven inflammation, however, have diametrically opposed effects on immunity. Understanding links may unlock novel immunotherapeutic paradigms treat cancer.

Язык: Английский

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DNA damage response inhibitors: Mechanisms and potential applications in cancer therapy

Cancer Treatment Reviews, Год журнала: 2017, Номер 60, С. 139 - 151

Опубликована: Сен. 19, 2017

Язык: Английский

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

Molecular Cancer Therapeutics, Год журнала: 2019, Номер 19(1), С. 13 - 25

Опубликована: Сен. 18, 2019

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

Язык: Английский

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Variant classification in precision oncology

International Journal of Cancer, Год журнала: 2019, Номер 145(11), С. 2996 - 3010

Опубликована: Апрель 22, 2019

Next‐generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool translational oncology. Its rapidly increasing use during the last decade expanded options for targeted tumor therapies, molecular boards have grown accordingly. However, with detection genetic alterations, their interpretation more complex error‐prone, potentially introducing biases reducing benefits clinical practice. To facilitate interdisciplinary discussions alterations treatment stratification between pathologists, oncologists, bioinformaticians, counselors medical scientists specialized boards, several systems classification variants detected by large‐scale been proposed. We review three recent commonly applied classifications discuss individual strengths weaknesses. Comparison underlines need clinically useful universally applicable variant reporting system, which will be instrumental efficient decision making based on analysis Integrating these data, we propose generalizable concept featuring conservative progressive scheme, can readily setting.

Язык: Английский

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Exploiting DNA repair defects in colorectal cancer

Molecular Oncology, Год журнала: 2019, Номер 13(4), С. 681 - 700

Опубликована: Фев. 4, 2019

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. Therapies that take advantage defects in DNA repair pathways have been explored context breast, ovarian, and other tumor types, but not yet systematically CRC. At present, only immune checkpoint blockade therapies FDA approved for use mismatch repair-deficient colorectal tumors. Here, we discuss how systematic identification alterations genes could provide new therapeutic opportunities CRCs. Analysis The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) Rectal (TCGA-READ) PanCancer datasets identified 141 (out 528) cases with putative driver mutations 29 associated damage response repair, including homologous recombination pathways. Genetic these might confer characteristics, such as genomic instability absence recombination, which can be exploited. For example, inhibitors poly(ADP)-ribose polymerase are effectively used to treat cancers carry BRCA1 and/or BRCA2 shown promising results CRC preclinical studies. HR deficiency also occur cells no detectable BRCA1/BRCA2 exhibiting BRCA-like phenotypes. repair-targeting therapies, ATR CHK1 (which most effective against carrying ATM mutations), combination current genotoxic chemotherapies CRCs further improve therapy response. Finally, target alternative mechanisms, thiopurines, potential increased sensitivity chemotherapy regimens, thus expanding spectrum options potentially improving clinical outcomes patients.

Язык: Английский

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