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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Authors
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
Valeri, N
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
Valeri, N
Document Type
Journal Article
Date
2024-05-15
Date Accepted
2024-02-16
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.
Citation
Clinical Cancer Research, 2024, pp. OF1 - OF20
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
1557-3265
1557-3265
Collections
Research Team
Medicine (RMH)
Paediatric Tumour Biology
Breast Epige Plast & Evol
GI Cancer Biol & Genomics
Paediatric Tumour Biology
Breast Epige Plast & Evol
GI Cancer Biol & Genomics