Cargando…

Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy

The ataxia telangiectasia mutated serine/threonine kinase (ATM)/checkpoint kinase 2 (CHEK2, best known as CHK2) and the ATM and Rad3-related serine/threonine kinase (ATR)/CHEK1 (best known as CHK1) cascades are the 2 major signaling pathways driving the DNA damage response (DDR), a network of proces...

Descripción completa

Detalles Bibliográficos
Autores principales: Manic, Gwenola, Obrist, Florine, Sistigu, Antonella, Vitale, Ilio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905354/
https://www.ncbi.nlm.nih.gov/pubmed/27308506
http://dx.doi.org/10.1080/23723556.2015.1012976
_version_ 1782437252497932288
author Manic, Gwenola
Obrist, Florine
Sistigu, Antonella
Vitale, Ilio
author_facet Manic, Gwenola
Obrist, Florine
Sistigu, Antonella
Vitale, Ilio
author_sort Manic, Gwenola
collection PubMed
description The ataxia telangiectasia mutated serine/threonine kinase (ATM)/checkpoint kinase 2 (CHEK2, best known as CHK2) and the ATM and Rad3-related serine/threonine kinase (ATR)/CHEK1 (best known as CHK1) cascades are the 2 major signaling pathways driving the DNA damage response (DDR), a network of processes crucial for the preservation of genomic stability that act as a barrier against tumorigenesis and tumor progression. Mutations and/or deletions of ATM and/or CHK2 are frequently found in tumors and predispose to cancer development. In contrast, the ATR–CHK1 pathway is often upregulated in neoplasms and is believed to promote tumor growth, although some evidence indicates that ATR and CHK1 may also behave as haploinsufficient oncosuppressors, at least in a specific genetic background. Inactivation of the ATM–CHK2 and ATR–CHK1 pathways efficiently sensitizes malignant cells to radiotherapy and chemotherapy. Moreover, ATR and CHK1 inhibitors selectively kill tumor cells that present high levels of replication stress, have a deficiency in p53 (or other DDR players), or upregulate the ATR–CHK1 module. Despite promising preclinical results, the clinical activity of ATM, ATR, CHK1, and CHK2 inhibitors, alone or in combination with other therapeutics, has not yet been fully demonstrated. In this Trial Watch, we give an overview of the roles of the ATM-CHK2 and ATR-CHK1 pathways in cancer initiation and progression, and summarize the results of clinical studies aimed at assessing the safety and therapeutic profile of regimens based on inhibitors of ATR and CHK1, the only 2 classes of compounds that have so far entered clinics.
format Online
Article
Text
id pubmed-4905354
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Taylor & Francis
record_format MEDLINE/PubMed
spelling pubmed-49053542016-06-15 Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy Manic, Gwenola Obrist, Florine Sistigu, Antonella Vitale, Ilio Mol Cell Oncol Review The ataxia telangiectasia mutated serine/threonine kinase (ATM)/checkpoint kinase 2 (CHEK2, best known as CHK2) and the ATM and Rad3-related serine/threonine kinase (ATR)/CHEK1 (best known as CHK1) cascades are the 2 major signaling pathways driving the DNA damage response (DDR), a network of processes crucial for the preservation of genomic stability that act as a barrier against tumorigenesis and tumor progression. Mutations and/or deletions of ATM and/or CHK2 are frequently found in tumors and predispose to cancer development. In contrast, the ATR–CHK1 pathway is often upregulated in neoplasms and is believed to promote tumor growth, although some evidence indicates that ATR and CHK1 may also behave as haploinsufficient oncosuppressors, at least in a specific genetic background. Inactivation of the ATM–CHK2 and ATR–CHK1 pathways efficiently sensitizes malignant cells to radiotherapy and chemotherapy. Moreover, ATR and CHK1 inhibitors selectively kill tumor cells that present high levels of replication stress, have a deficiency in p53 (or other DDR players), or upregulate the ATR–CHK1 module. Despite promising preclinical results, the clinical activity of ATM, ATR, CHK1, and CHK2 inhibitors, alone or in combination with other therapeutics, has not yet been fully demonstrated. In this Trial Watch, we give an overview of the roles of the ATM-CHK2 and ATR-CHK1 pathways in cancer initiation and progression, and summarize the results of clinical studies aimed at assessing the safety and therapeutic profile of regimens based on inhibitors of ATR and CHK1, the only 2 classes of compounds that have so far entered clinics. Taylor & Francis 2015-02-23 /pmc/articles/PMC4905354/ /pubmed/27308506 http://dx.doi.org/10.1080/23723556.2015.1012976 Text en © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
spellingShingle Review
Manic, Gwenola
Obrist, Florine
Sistigu, Antonella
Vitale, Ilio
Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy
title Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy
title_full Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy
title_fullStr Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy
title_full_unstemmed Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy
title_short Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy
title_sort trial watch: targeting atm–chk2 and atr–chk1 pathways for anticancer therapy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905354/
https://www.ncbi.nlm.nih.gov/pubmed/27308506
http://dx.doi.org/10.1080/23723556.2015.1012976
work_keys_str_mv AT manicgwenola trialwatchtargetingatmchk2andatrchk1pathwaysforanticancertherapy
AT obristflorine trialwatchtargetingatmchk2andatrchk1pathwaysforanticancertherapy
AT sistiguantonella trialwatchtargetingatmchk2andatrchk1pathwaysforanticancertherapy
AT vitaleilio trialwatchtargetingatmchk2andatrchk1pathwaysforanticancertherapy