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Supplementary Figure S2 from 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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posted on 2024-05-15, 07:22 authored by Somaieh Hedayat, Luciano Cascione, David Cunningham, Marta Schirripa, Andrea Lampis, Jens C. Hahne, Nina Tunariu, Sung Pil Hong, Silvia Marchetti, Khurum Khan, Elisa Fontana, Valentina Angerilli, Mia Delrieux, Daniel Nava Rodrigues, Letizia Procaccio, Sheela Rao, David Watkins, Naureen Starling, Ian Chau, Chiara Braconi, Nicos Fotiadis, Ruwaida Begum, Naomy Guppy, Louise Howell, Melanie Valenti, Scott Cribbes, Bernadett Kolozsvari, Vladimir Kirkin, Sara Lonardi, Michele Ghidini, Rodolfo Passalacqua, Raghad Elghadi, Luca Magnani, David J. Pinato, Federica Di Maggio, Filippo Ghelardi, Elisa Sottotetti, Guglielmo Vetere, Paolo Ciracì, Georgios Vlachogiannis, Filippo Pietrantonio, Chiara Cremolini, Alessio Cortellini, Fotios Loupakis, Matteo Fassan, Nicola Valeri

Supplementary Figure S2. Changes in MIR652-3p expression upon anti-angiogenic treatment.

Funding

Cancer Research UK (CRUK)

History

ARTICLE ABSTRACT

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. 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. 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. Our results identify MIR652–3p as a potential biomarker and as a driver of cell and non–cell-autonomous mechanisms of resistance to regorafenib.