miR-196b strictly regulates and reliably predicts the response to cetuximab in colorectal cancer.

Abstract

Background: Cetuximab resistance severely restricts its effectiveness in the treatment of patients with metastatic colorectal cancer (CRC). Previous studies have predominantly focused on the genetic level, with scant attention to the nongenetic aspects. This study aimed to identify the crucial microRNA (miRNA) that is responsible for cetuximab resistance.

Methods: Key miRNAs were identified using small RNA sequencing analysis. miR-196b's role and mechanism in cetuximab resistance was explored by in vitro and in vivo experiments. Clinical blood samples were dynamically analyzed using droplet digital polymerase chain reaction (PCR) to assess the predictive value of miR-196b for efficacy.

Results: We initially discovered that the extracellular signal-regulated kinase (ERK) signaling pathway was progressively activated during the acquisition of cetuximab resistance in CRC cells. Further study determined that miR-196b can inhibit the activity of ERK and protein kinase B (AKT) signaling pathways by downregulating both NRAS and BRAF, which can kill two birds with one stone, thus enhancing the sensitivity of colorectal cancer cells to cetuximab. The expression of miR-196b was found to be significantly downregulated in both cetuximab-resistant cells and the tumor tissues of patients exhibiting resistance. In the presence of cetuximab, overexpression of miR-196b further inhibited the proliferation and migration and promoted the apoptosis of CRC cells, while miR-196b silencing had the opposite effects. Importantly, analysis of clinical blood samples confirmed that miR-196b can serve as a predictive and dynamic biomarker for monitoring the outcomes of patients with CRC treated with cetuximab.

Conclusions: This study supports that activation of the ERK signaling pathway is a key factor in cetuximab resistance. In addition, miR-196b can modulate and predict the CRC response to cetuximab, holding broad potential applications.