Abstract LB-305: Circulating miR-652-3p as a biomarker of resistance to regorafenib in metastatic colorectal cancer patients

Abstract

Abstract MicroRNAs (miRs) are small non-coding RNAs involved in cell homeostasis and carcinogenesis and control multiple oncogenic pathways. Numerous miRs are aberrantly expressed in colorectal cancer (CRC) and their deregulation is associated with clinical outcome and cancer progression. Chemo-refractory metastatic CRC (mCRC) patients are often treated with regorafenib, a multi-tyrosine kinase inhibitor with anti-angiogenic effect. Given the limited clinical benefits of regorafenib in unselected patient populations, there is an unmet need for better patient selection and identification of mechanisms of resistance. miRs are highly stable and have shown encouraging value as potential biomarkers for CRC detection and prognosis. Here we aimed to identify circulatory miRs that might be exploited for the upfront selection of patients’ candidate to regorafenib treatment. We ran a translational phase II trial of regorafenib in chemo-refractory mCRC patients. Serum, plasma and tissue biopsies were obtained at baseline (BL), every four weeks and at disease progression (PD). Patient Derived Organoids (PDOs) and PDO-xenotransplants were generated to study primary and acquired resistance to regorafenib. MiR profiling was performed in baseline serum of all patients by NanoString nCounter platform of 800 genes and validated with digital droplet (dd)PCR in serum, plasma, PDOs and by In Situ Hybridization (ISH) in matching tissue biopsies. Progression Free Survival (PFS) was measured from date of registration to date of first progression/relapse or death from cancer progression. Overall Survival (OS) was measured from date of randomisation to death from cancer. Further validation was performed by ddPCR in 97 patients from an independent patient’s cohort. MiR expression was tested in 43 BL sera and dysregulation in 28 miRs was associated with PFS and OS. Up-regulation of miR-652-3p was associated with worse PFS and OS. These results were validated by ddPCR on the same serum samples, and matching plasmas. ISH confirmed upregulation of this miR in sequential tissues biopsies, PDOs and PDO-xenotransplants of patients with primary and acquired resistance to regorafenib. Validation in an independent patient’s cohort confirmed direct association of miR-652-3p dysregulation with PFS and OS. Functional experiments to define miR652-3p mediated resistance have shown that there is a decrease of tumour growth and migration in miR-652-3p inhibition in PDOs. We provide initial evidence suggesting that circulating miR-652-3p might work as a negative predictive biomarker for the upfront selection of patients’ candidate to regorafenib treatment. Citation Format: Somaieh Hedayat, Khurum Khan, David Cunningham, George Vlachogiannis, Andrea Lampis, Silvia Marchetti, Matteo Fassan, Ruwaida Begum, Marta Schirripa, Fotios Fotios Loupakis, Nicola Valeri. Circulating miR-652-3p as a biomarker of resistance to regorafenib in metastatic colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-305.