Targeting of TP53-independent cell cycle checkpoints overcomes FOLFOX resistance in Metastatic Colorectal Cancer
Targeting of TP53-independent cell cycle checkpoints overcomes FOLFOX resistance in Metastatic Colorectal Cancer
ABSTRACT Patients with colorectal cancer (CRC) frequently develop liver metastases during the course of their disease. A substantial proportion of them receive neoadjuvant FOLFOX (5-Fluorouracil, Oxaliplatin, Leucovorin) prior to surgery in an attempt to enable successful surgical removal of their metastases and to reduce the risk of recurrence. Yet, the majority of patients progress during treatment or recur following surgery, and molecular mechanisms that contribute to FOLFOX resistance remain poorly understood. Here, using a combination of phenotypic, transcriptomic and genomic analyses of both tumor samples derived from patients with metastatic CRC and matching patient-derived tumor organoids (PDTOs), we characterize a novel FOLFOX resistance mechanism and identify inhibitors that target this mechanism to resensitize metastatic organoids to FOLFOX. Resistant PDTOs, identified after in vitro exposure to FOLFOX, exhibited elevated expression of E2F pathway, S phase, G2/M and spindle assembly checkpoints (SAC) genes. Similar molecular features were detected in CRLM from patients with progressive disease while under neoadjuvant FOLFOX treatment, highlighting the relevance of this finding. FOLFOX resistant PDTOs displayed inactivating mutations of TP53 and exhibited transcriptional features of P53 pathway downregulation. We found that they accumulated in early S-phase and underwent significant DNA damage during FOLFOX exposure, thereafter arresting in G2/M while they repaired their DNA after FOLFOX withdrawal. In parallel, results of a large kinase inhibitor screen indicated that drugs targeting regulators of the DNA damage response, G2M checkpoint and SAC had cytotoxic effects on PDTOs generated from patients whose disease progressed during treatment with FOLFOX. Corroborating this finding, CHK1 and WEE1 inhibitors were found to synergize with FOLFOX and sensitize previously resistant PDTOs. Additionally, targeting the SAC master regulator MPS1 using empesertib after exposure to FOLFOX, when cells accumulate in G2M, was also very effective to kill FOLFOX-resistant PDTOs. Our results indicate that targeted and timely inhibition of specific cell cycle checkpoints shows great potential to improve response rates to FOLFOX in patients with metastatic CRC, for whom therapeutic alternatives remain extremely limited.
Nikolic Iva、Millen Rosie、Patch Ann-Marie、Foroutan Momeneh、Lind Phoebe、Grandin M¨|lodie、Shembrey Carolyn、Luu Jennii、Cursons Joseph、Knowles Brett、Grimmond Sean M.、Heriot Alexander G.、Michael Michael、Simpson Kaylene、Cowley Karla、Puisieux Alain、Hollande Fr¨|d¨|ric、Smith Jai、Behrenbruch Corina、Huntington Nicholas D.、Ramsay Robert G.、Thomson Benjamin NJ.、Cooper Benjamin、Ramm Susanne
The University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Victorian Centre for Functional Genomics, Peter MacCallum Cancer CentreThe University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Peter MacCallum Cancer CentreQIMRThe University of Melbourne, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre||University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre||Biomedicine Discovery Institute, Monash UniversityThe University of Melbourne, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre||University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer CentreThe University of Melbourne, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre||University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer CentreThe University of Melbourne, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre||University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer CentreThe University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Victorian Centre for Functional Genomics, Peter MacCallum Cancer CentreBiomedicine Discovery Institute, Monash UniversityDepartment of General Surgical Specialties, The Royal Melbourne Hospital||The University of Melbourne, Royal Melbourne Hospital Department of SurgeryThe University of Melbourne, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre||University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer CentreThe University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Department of Cancer Surgery, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre||The University of Melbourne, Department of Surgery, St Vincent?ˉs HospitalThe University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Department of Medical Oncology, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer CentreThe University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Victorian Centre for Functional Genomics, Peter MacCallum Cancer CentreThe University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Victorian Centre for Functional Genomics, Peter MacCallum Cancer CentreInstitut CurieThe University of Melbourne, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre||University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer CentreThe University of Melbourne, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre||University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer CentreThe University of Melbourne, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre||University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre||The University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Department of General Surgical Specialties, The Royal Melbourne HospitalBiomedicine Discovery Institute, Monash UniversityThe University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Peter MacCallum Cancer CentreDepartment of General Surgical Specialties, The Royal Melbourne Hospital||The University of Melbourne, Royal Melbourne Hospital Department of SurgeryThe University of Melbourne, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre||University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre||The University of Melbourne, Department of Pharmacology and Therapeutics, Medical BuildingThe University of Melbourne, Sir Peter MacCallum Department of Oncology, Victorian Comprehensive Cancer Centre||Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre
肿瘤学基础医学临床医学
Nikolic Iva,Millen Rosie,Patch Ann-Marie,Foroutan Momeneh,Lind Phoebe,Grandin M¨|lodie,Shembrey Carolyn,Luu Jennii,Cursons Joseph,Knowles Brett,Grimmond Sean M.,Heriot Alexander G.,Michael Michael,Simpson Kaylene,Cowley Karla,Puisieux Alain,Hollande Fr¨|d¨|ric,Smith Jai,Behrenbruch Corina,Huntington Nicholas D.,Ramsay Robert G.,Thomson Benjamin NJ.,Cooper Benjamin,Ramm Susanne.Targeting of TP53-independent cell cycle checkpoints overcomes FOLFOX resistance in Metastatic Colorectal Cancer[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2021.02.04.429849.点此复制
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