1. 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.
- Author
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Hedayat S, Cascione L, Cunningham D, Schirripa M, Lampis A, Hahne JC, Tunariu N, Hong SP, Marchetti S, Khan K, Fontana E, Angerilli V, Delrieux M, Nava Rodrigues D, Procaccio L, Rao S, Watkins D, Starling N, Chau I, Braconi C, Fotiadis N, Begum R, Guppy N, Howell L, Valenti M, Cribbes S, Kolozsvari B, Kirkin V, Lonardi S, Ghidini M, Passalacqua R, Elghadi R, Magnani L, Pinato DJ, Di Maggio F, Ghelardi F, Sottotetti E, Vetere G, Ciracì P, Vlachogiannis G, Pietrantonio F, Cremolini C, Cortellini A, Loupakis F, Fassan M, and Valeri N
- Subjects
- 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, 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
- Abstract
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.)
- Published
- 2024
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