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
BACKGROUND: The multi-kinase inhibitor regorafenib has demonstrated efficacy in chemo-refractory metastatic colorectal cancer (mCRC) patients. However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice.
METHODS: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemo-refractory mCRC patients 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 (PDOs) 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 In Situ Hybridization 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 modelled 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 potential biomarker and as a driver of cell and non-cell autonomous mechanisms of resistance to regorafenib.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - (2024) vom: 20. Feb. |
| Sprache: |
Englisch |
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Date Revised 20.02.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1158/1078-0432.CCR-23-2748 |
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| PPN (Katalog-ID): |
NLM368669777 |
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| 100 | 1 | |a Hedayat, Somaieh |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 20.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a BACKGROUND: The multi-kinase inhibitor regorafenib has demonstrated efficacy in chemo-refractory metastatic colorectal cancer (mCRC) patients. However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice | ||
| 520 | |a METHODS: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemo-refractory mCRC patients 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 (PDOs) 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 In Situ Hybridization in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses | ||
| 520 | |a 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 modelled 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 | ||
| 520 | |a CONCLUSIONS: Our results identify MIR652-3p as potential biomarker and as a driver of cell and non-cell autonomous mechanisms of resistance to regorafenib | ||
| 650 | 4 | |a Journal Article | |
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