دورية أكاديمية
Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652-3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer.
| العنوان: | Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652-3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer. |
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| المؤلفون: | Hedayat S; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom., Cascione L; Bioinformatics Core Unit, Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland.; Swiss Institute of Bioinformatics, Bellinzona, Switzerland., Cunningham D; Department of Medicine, The Royal Marsden Hospital, London and Sutton, United Kingdom., Schirripa M; Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy., Lampis A; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom., Hahne JC; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom., Tunariu N; Department of Radiology, The Royal Marsden Hospital, London and Sutton, United Kingdom., Hong SP; Division of Surgery and Cancer, Imperial College London, London, United Kingdom., Marchetti S; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom., Khan K; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.; Department of Medicine, The Royal Marsden Hospital, London and Sutton, United Kingdom., Fontana E; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom., Angerilli V; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.; Department of Medicine, Surgical Pathology Unit, University of Padua, Padua, Italy., Delrieux M; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom., Nava Rodrigues D; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom., Procaccio L; Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy., Rao S; Department of Medicine, The Royal Marsden Hospital, London and Sutton, United Kingdom., Watkins D; Department of Medicine, The Royal Marsden Hospital, London and Sutton, United Kingdom., Starling N; Department of Medicine, The Royal Marsden Hospital, London and Sutton, United Kingdom., Chau I; Department of Medicine, The Royal Marsden Hospital, London and Sutton, United Kingdom., Braconi C; Department of Medicine, The Royal Marsden Hospital, London and Sutton, United Kingdom.; Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Fotiadis N; Department of Interventional Radiology, The Royal Marsden Hospital, London, United Kingdom., Begum R; Department of Medicine, The Royal Marsden Hospital, London and Sutton, United Kingdom., Guppy N; Breast Cancer Now Nina Barough Pathology Core Facility, The Institute of Cancer Research, London, United Kingdom., Howell L; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom., Valenti M; Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Cribbes S; Revvity, Waltham, Massachusetts., Kolozsvari B; Sartorius, London, United Kingdom., Kirkin V; Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Lonardi S; Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy., Ghidini M; Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., Passalacqua R; Oncology Unit, ASST Cremona, Cremona, Italy., Elghadi R; Division of Surgery and Cancer, Imperial College London, London, United Kingdom., Magnani L; Division of Surgery and Cancer, Imperial College London, London, United Kingdom., Pinato DJ; Division of Surgery and Cancer, Imperial College London, London, United Kingdom.; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy., Di Maggio F; Division of Surgery and Cancer, Imperial College London, London, United Kingdom.; Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.; CEINGE-Biotecnologie Avanzate Francesco Salvatore, Via Gaetano Salvatore, Naples, Italy., Ghelardi F; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Sottotetti E; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Vetere G; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Ciracì P; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Vlachogiannis G; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.; Division of Surgery and Cancer, Imperial College London, London, United Kingdom., Pietrantonio F; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Cremolini C; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy., Cortellini A; Division of Surgery and Cancer, Imperial College London, London, United Kingdom.; Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy., Loupakis F; Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy., Fassan M; Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy.; Department of Medicine, Surgical Pathology Unit, University of Padua, Padua, Italy., Valeri N; Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.; Department of Medicine, The Royal Marsden Hospital, London and Sutton, United Kingdom.; Division of Surgery and Cancer, Imperial College London, London, United Kingdom. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 May 15; Vol. 30 (10), pp. 2140-2159. |
| نوع المنشور: | Journal Article; Clinical Trial, Phase II; Multicenter Study |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Colorectal Neoplasms*/drug therapy , Colorectal Neoplasms*/genetics , Colorectal Neoplasms*/pathology , Colorectal Neoplasms*/blood , Phenylurea Compounds*/pharmacology , Phenylurea Compounds*/therapeutic use , Pyridines*/therapeutic use , Pyridines*/pharmacology , Drug Resistance, Neoplasm*/genetics , Biomarkers, Tumor*/genetics , Biomarkers, Tumor*/blood , Circulating MicroRNA*, Humans ; Animals ; Female ; Prospective Studies ; Male ; Mice ; Xenograft Model Antitumor Assays ; Gene Expression Regulation, Neoplastic/drug effects ; Aged ; Liquid Biopsy/methods ; Middle Aged ; Cell Line, Tumor ; MicroRNAs/genetics ; MicroRNAs/blood |
| مستخلص: | Purpose: The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. Experimental Design: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. Results: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652-3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a "control" group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652-3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. Conclusions: Our results identify MIR652-3p as a potential biomarker and as a driver of cell and non-cell-autonomous mechanisms of resistance to regorafenib. (©2024 American Association for Cancer Research.) |
| معلومات مُعتمدة: | A18052 Cancer Research UK (CRUK); A26815 Cancer Research UK (CRUK) |
| تواريخ الأحداث: | Date Created: 20240220 Date Completed: 20240515 Latest Revision: 20240612 |
| رمز التحديث: | 20240613 |
| DOI: | 10.1158/1078-0432.CCR-23-2748 |
| PMID: | 38376926 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-23-2748 |