Exploiting the weak link: Ataxia-Telangiectasia Mutated
dysfunction in oesophagogastric tumours

J 2026

Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours

TRYBALA, Zuzanna; Giulia COSTELLA; Kristína BEDNÁROVÁ; Lukasz ARCIMOWICZ; Achim AIGNER et al.

Základní údaje

Originální název

Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours

Autoři

TRYBALA, Zuzanna; Giulia COSTELLA; Kristína BEDNÁROVÁ ; Lukasz ARCIMOWICZ; Achim AIGNER; Florian LORDICK; Radka LORDICK OBERMANNOVÁ a Petr MULLER

Vydání

CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, NEW YORK, ELSEVIER SCIENCE INC, 2026, 1040-8428

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.600 v roce 2024

Označené pro přenos do RIV

Ano

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

ATM; Oesophagogastric cancer; DNA damage response; Biomarkers; ATR inhibitors; Synthetic lethality; Precision oncology

Štítky

14110811, 14314010

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 5. 10. 2026 10:06, Mgr. Tereza Miškechová

Anotace

V originále

ATM (ataxia-telangiectasia mutated) is a central regulator of the DNA damage response, coordinating double-strand break repair, checkpoint control, and cell fate decisions. Its disruption drives genomic instability and has been implicated across multiple tumour types. In oesophagogastric cancers, ATM alterations occur in a clinically relevant subset of cases, encompassing both somatic and germline events, and are associated with distinct molecular features including reduced co-occurrence with TP53 mutations and elevated homologous recombination deficiency scores. This narrative review synthesises published literature and publicly available genomic databases to examine ATM biology, the spectrum of ATM alterations across oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cancer subtypes, and the challenges of defining true ATM deficiency. The therapeutic implications of ATM dysfunction are evaluated across radiotherapy, platinum-based chemotherapy, ATR inhibition, and PARP inhibition. ATM alterations are detected in approximately 6% of tumours pan-cancer and in up to 10% of oesophagogastric cases. Defining ATM deficiency remains challenging, as immunohistochemistry, next-generation sequencing, and functional assays each carry distinct limitations. ATR inhibition emerges as the most consistently supported therapeutic strategy, with converging preclinical and early clinical evidence across oesophagogastric models. By contrast, available data do not support treating ATM deficiency as equivalent to BRCA-like homologous recombination deficiency, and PARP inhibitor monotherapy has not demonstrated consistent benefit. Prospective validation of functional ATM assays, histology-stratified trial design, and integration of genomic, protein-level, and functional evidence represent key priorities for translating ATM-guided strategies into oesophagogastric cancer practice.

Návaznosti

EH22_008/0004644, projekt VaV

Název: Záchrana životů prostřednictvím výzkumu v oblasti včasné detekce a prevence rakoviny: Molekulární, genomické a sociální faktory

Citovat

TRYBALA, Zuzanna; Giulia COSTELLA; Kristína BEDNÁROVÁ; Lukasz ARCIMOWICZ; Achim AIGNER; Florian LORDICK; Radka LORDICK OBERMANNOVÁ a Petr MULLER. Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours. CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY. NEW YORK: ELSEVIER SCIENCE INC, 2026, roč. 226, October 2026, s. 1-15. ISSN 1040-8428. Dostupné z: https://doi.org/10.1016/j.critrevonc.2026.105503.

@article{2591521,
   author = {Trybala, Zuzanna and Costella, Giulia and Bednárová, Kristína and Arcimowicz, Lukasz and Aigner, Achim and Lordick, Florian and Lordick Obermannová, Radka and Muller, Petr},
   article_location = {NEW YORK},
   article_number = {October 2026},
   doi = {https://doi.org/10.1016/j.critrevonc.2026.105503},
   keywords = {ATM; Oesophagogastric cancer; DNA damage response; Biomarkers; ATR inhibitors; Synthetic lethality; Precision oncology},
   language = {eng},
   issn = {1040-8428},
   journal = {CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY},
   title = {Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours},
   url = {https://www.sciencedirect.com/science/article/pii/S1040842826003902?via%3Dihub},
   volume = {226},
   year = {2026}
}

TY  - JOUR
ID  - 2591521
AU  - Trybala, Zuzanna - Costella, Giulia - Bednárová, Kristína - Arcimowicz, Lukasz - Aigner, Achim - Lordick, Florian - Lordick Obermannová, Radka - Muller, Petr
PY  - 2026
TI  - Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours
JF  - CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
VL  - 226
IS  - October 2026
SP  - 1-15
EP  - 1-15
PB  - ELSEVIER SCIENCE INC
SN  - 10408428
KW  - ATM
KW  - Oesophagogastric cancer
KW  - DNA damage response
KW  - Biomarkers
KW  - ATR inhibitors
KW  - Synthetic lethality
KW  - Precision oncology
UR  - https://www.sciencedirect.com/science/article/pii/S1040842826003902?via%3Dihub
N2  - ATM (ataxia-telangiectasia mutated) is a central regulator of the DNA damage response, coordinating double-strand break repair, checkpoint control, and cell fate decisions. Its disruption drives genomic instability and has been implicated across multiple tumour types. In oesophagogastric cancers, ATM alterations occur in a clinically relevant subset of cases, encompassing both somatic and germline events, and are associated with distinct molecular features including reduced co-occurrence with TP53 mutations and elevated homologous recombination deficiency scores. This narrative review synthesises published literature and publicly available genomic databases to examine ATM biology, the spectrum of ATM alterations across oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cancer subtypes, and the challenges of defining true ATM deficiency. The therapeutic implications of ATM dysfunction are evaluated across radiotherapy, platinum-based chemotherapy, ATR inhibition, and PARP inhibition. ATM alterations are detected in approximately 6% of tumours pan-cancer and in up to 10% of oesophagogastric cases. Defining ATM deficiency remains challenging, as immunohistochemistry, next-generation sequencing, and functional assays each carry distinct limitations. ATR inhibition emerges as the most consistently supported therapeutic strategy, with converging preclinical and early clinical evidence across oesophagogastric models. By contrast, available data do not support treating ATM deficiency as equivalent to BRCA-like homologous recombination deficiency, and PARP inhibitor monotherapy has not demonstrated consistent benefit. Prospective validation of functional ATM assays, histology-stratified trial design, and integration of genomic, protein-level, and functional evidence represent key priorities for translating ATM-guided strategies into oesophagogastric cancer practice.
ER  -

TRYBALA, Zuzanna; Giulia COSTELLA; Kristína BEDNÁROVÁ; Lukasz ARCIMOWICZ; Achim AIGNER; Florian LORDICK; Radka LORDICK OBERMANNOVÁ a Petr MULLER. Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours. \textit{CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY}. NEW YORK: ELSEVIER SCIENCE INC, 2026, roč.~226, October 2026, s.~1-15. ISSN~1040-8428. Dostupné z: https://doi.org/10.1016/j.critrevonc.2026.105503.

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