MicroRNAs as biomarkers of response to HER2 inhibitors in gastro-oesophageal cancers

Abstract

Trastuzumab in combination with chemotherapy represents the standard of care in HER2-positive advanced gastro-oesophageal cancer (GOC), but development of resistance limits response. MicroRNAs (miRs) modulate key pathways in GOC and may be involved in primary resistance to HER2 inhibitors. MicroRNAs may represent a clinically useful biomarker for gastro-oesophageal cancer (GOC) patients with HER2 positive disease. Identification of miRs responsible for resistance to HER2 inhibition may help stratify patients, predict response, minimise chances of severe toxicity in those less likely to respond, and define novel strategies to restore drug sensitivity. This project aims to identify microRNAs associated with resistance to HER2 inhibitors in vitro by using a high-throughput response in GOC cell lines to identify potential miRs involved in trastuzumab sensitivity/resistance. Putative hits are validated and explored in translational samples from the MAGIC trial (ISRCTN93793971), FOrMAT trial (NCT02112357) and PLATFORM trial (NCT02678182). My screen identifies a panel of miRs associated with GOC resistance to HER2 inhibitors in combination with chemotherapy. Inhibition of these miRs affects GOC cell viability and restores sensitivity. MiR-148a-3p has emerged as a potential biomarker as a potential biomarker of resistance in GOC patients.