Micrornas As Biomarkers Of Resistance To Her2 Inhibition In Combination With Chemotherapy In Gastro-Esophageal Cancer

Trastuzumab in combination with chemotherapy represents the standard of care in HER2-positive advanced gastro-esphageal cancer (GOC), but development of resistance limits response. MicroRNAs (miRs) modulate key pathways in GOC. Identification of miRs responsible for resistance to HER2 inhibition may help stratify patients, predict response and define novel strategies to restore drug sensitivity. A high-throughput LNA™ miR-inhibitor screen in HER2-positive NCI-N87 and HER2-negative FLO-1 GOC cell lines was performed in order to identify potential miRs involved in trastuzumab sensitivity/resistance. Cells were treated with a combination of cisplatin, 5FU, and trastuzumab. MiRs were considered significant if LNAs caused \u003e40% reduction in cell viability 72 hours post treatment relative to controls with a t-test p-value of In NCI-N87 and FLO-1 cell lines, 59 and 37 LNAs respectively caused \u003e40% reduction in cell viability compared to controls (p Our screen identified 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 emerged as a potential biomarker of resistance and further evaluation is underway in the PLATFORM trial (NCT02678182). Citation Format: Hazel Lote, Andrea Lampis, George Vlachogiannis, Jens Hahne, Sing-Yu Moorcraft, Michael Davidson, Carolin Fong, Ruwaida Begum, Matteo Fassan, Sheela Rao, David Watkins, Naureen Starling, Ian Chau, David Cunningham, Nicola Valeri. MicroRNAs as biomarkers of resistance to HER2 inhibition in combination with chemotherapy in gastro-esophageal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 258.