The use of miR-5193 to predict oxaliplatin chemosensitivity in colorectal cancer: Integrated in silico, in vitro, and clinical evidence.

Abstract

3527 Background: Outcomes with first-line chemotherapy in metastatic colorectal cancer (mCRC) are heterogeneous. We evaluated whether tumor microRNA miR-5193 is a predictive marker of chemosensitivity. Methods: We performed (i) a discovery analysis in TCGA COAD/READ to test associations between tumor miR-5193 and progression-free (PFS) and overall survival (OS) by Kaplan–Meier/log-rank; (ii) functional assays in colonic epithelium (CON-841) and colorectal cancer cell lines (Caco-2, HCT116) after miR-5193 mimic transfection, assessing 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) sensitivity by MTT and IC50; and (iii) a validation cohort of formalin-fixed paraffin-embedded (FFPE) primary tumors from Chilean mCRC patients (n=50) in which hsa-miR-5193 was quantified by RT-qPCR. Patients were dichotomized into low vs high expression, and PFS/OS were estimated by Kaplan–Meier/log-rank in the overall cohort and in prespecified oxaliplatin- and irinotecan-based first-line subgroups. Results: In TCGA mCRC cases selected for standard clinicopathologic features and chemotherapy exposure, low tumor miR-5193 expression was associated with shorter PFS (p=0.03). In vitro, miR-5193 was downregulated in CRC lines vs CON-841, and transient miR-5193 overexpression increased chemosensitivity to 5-FU (Caco-2; reduced viability at 200–250 µM and IC50 from 1138 to 345 µM, p=0.049) and oxaliplatin (HCT116; left-shifted dose–response and ~30–35% IC50 reduction, p<0.01). In the Chilean validation cohort, low (n=30) vs high (n=20) hsa-miR-5193 expression was associated with inferior OS (p=0.0081) and showed no statistically significant difference in PFS (p=0.058). Among patients receiving oxaliplatin-based first-line chemotherapy (FOLFOX/CAPEOX), low hsa-miR-5193 predicted shorter PFS (p=0.012), whereas no PFS difference was observed with irinotecan-based regimens (p=0.8104) (Table 1). Conclusions: miR-5193 appears to modulate chemosensitivity in mCRC. Low tumor miR-5193 is linked to reduced oxaliplatin and 5-FU sensitivity in vitro, and shorter PFS/OS under oxaliplatin-based therapy, supporting its role as a biomarker of oxaliplatin sensitivity. Prospective validation could enable miR-5193-guided treatment selection and risk stratification, particularly for patients considered for oxaliplatin-containing regimens. Association between hsa-miR-5193 expression and clinical outcomes in metastatic colorectal cancer. Study cohort / subgroup Outcome miR5193 expression: Low (n=30) vs high (n=20) P-value Chilean validation cohort – Overall PFS No significant difference 0,058 (NS) Chilean validation cohort – Overall OS Shorter OS 0,0081 FOLFOX/CAPEOX subgroup (oxaliplatin-based) PFS Shorter PFS 0,012 Irinotecan-based subgroup PFS No difference 0,8104 (NS)