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Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652-3p as a Response Biomarker and
Somaieh Hedayat1, Luciano Cascione2,3, David Cunningham4
1Division of Molecular Pathology and Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.
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.
Insights
Regorafenib shows promise in metastatic colorectal cancer, but lacks predictive biomarkers. MIR652-3p was identified as a biomarker predicting response and driving resistance to regorafenib by affecting autophagy and angiogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Regorafenib is a multi-kinase inhibitor (mKi) effective in chemorefractory metastatic colorectal cancer (mCRC).
- Predictive biomarkers and toxicity concerns limit regorafenib's clinical application.
Purpose of the Study:
- To identify predictive biomarkers for regorafenib efficacy in mCRC.
- To elucidate mechanisms of regorafenib resistance.
Main Methods:
- MicroRNA profiling of longitudinal liquid and tissue biopsies from mCRC patients treated with regorafenib.
- Establishment and analysis of patient-derived organoids (PDOs).
- Ex vivo co-culture assays and single-cell RNA-sequencing.
Main Results:
- MIR652-3p identified as a biomarker of clinical benefit to regorafenib in mCRC.
- MIR652-3p confirmed in validation cohorts and in patients treated with lonsurf.
- MIR652-3p impairs regorafenib-induced autophagy and promotes angiogenesis-related resistance mechanisms.
Conclusions:
- MIR652-3p is a potential predictive biomarker for regorafenib treatment in mCRC.
- MIR652-3p drives both cell-autonomous and non-cell-autonomous resistance to regorafenib.
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