Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer.

Autor:	Durinikova E; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy., Reilly NM; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy., Buzo K; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy., Mariella E; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy., Chilà R; Department of Oncology, University of Torino, Candiolo, Italy.; IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy., Lorenzato A; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy., Dias JML; Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.; Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom., Grasso G; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy., Pisati F; Histopathology Unit, Cogentech, Milan, Italy., Lamba S; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy., Corti G; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy., Degasperi A; Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.; Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom., Cancelliere C; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy., Mauri G; IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Andrei P; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy., Linnebacher M; Clinic of General Surgery, Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany., Marsoni S; IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy., Siena S; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy., Sartore-Bianchi A; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy., Nik-Zainal S; Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.; Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom., Di Nicolantonio F; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy., Bardelli A; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy., Arena S; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Candiolo, Italy.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Sep 01; Vol. 28 (17), pp. 3874-3889.
DOI:	10.1158/1078-0432.CCR-22-0875
Abstrakt:	Purpose: Genomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored. Experimental Design: We challenged 112 cell models recapitulating the genomic landscape of metastatic colorectal cancer with ATM, ATR, CHK1, WEE1, and DNA-PK inhibitors, in parallel with chemotherapeutic agents. We focused then on ATR inhibitors (ATRi) and, to identify putative biomarkers of response and resistance, we analyzed at multiple levels colorectal cancer models highly sensitive or resistant to these drugs. Results: We found that around 30% of colorectal cancers, including those carrying KRAS and BRAF mutations and unresponsive to targeted agents, are sensitive to at least one DDR inhibitor. By investigating potential biomarkers of response to ATRi, we found that ATRi-sensitive cells displayed reduced phospho-RPA32 foci at basal level, while ATRi-resistant cells showed increased RAD51 foci formation in response to replication stress. Lack of ATM and RAD51C expression was associated with ATRi sensitivity. Analysis of mutational signatures and HRDetect score identified a subgroup of ATRi-sensitive models. Organoids derived from patients with metastatic colorectal cancer recapitulated findings obtained in cell lines. Conclusions: In conclusion, a subset of colorectal cancers refractory to current therapies could benefit from inhibitors of DDR pathways and replication stress. A composite biomarker involving phospho-RPA32 and RAD51 foci, lack of ATM and RAD51C expression, as well as analysis of mutational signatures could be used to identify colorectal cancers likely to respond to ATRi. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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