1595P - MicroRNAs as biomarkers of resistance to HER2 inhibitors in combination with chemotherapy in gastro-oesophageal cancer cell lines

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Hazel Lote
Citation Annals of Oncology (2016) 27 (6): 545-551. 10.1093/annonc/mdw393
Authors H. Lote1, D. Zito1, R. Burke2, E. Smyth3, C. Braconi4, D. Cunningham5, N. Valeri6
  • 1Laboratory Of Gastrointestinal Cancer Biology And Genomics, Division Of Molecular Pathology, The Institute of Cancer Research ICR, SM2 5NG - Sutton/GB
  • 2Cancer Therapeutics, Institute of Cancer Research ICR, SM2 5NG - London/GB
  • 3Department Of Oncology, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, Sutton/GB
  • 4Signal Transduction And Molecular Pharmacology, The Institute of Cancer Research ICR, SM2 5NG - Sutton/GB
  • 5Department Of Oncology, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, SM2 5PT - Sutton/GB
  • 6Laboratory Of Gastrointestinal Cancer Biology And Genomics, Division Of Molecular Pathology, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, SM2 5NG - Sutton/GB

Abstract

Background

MicroRNAs (miRs) may be involved in primary resistance to HER2 inhibitors and represent a clinically useful biomarker for gastro-oesophageal cancer (GOC) patients with HER2 amplified disease. Identification of miRs responsible for resistance to HER2 inhibitors may allow us to develop a novel, reproducible, non-invasive and cost-effective tool for GOC patient stratification. Defining predictive biomarkers of resistance to HER2 inhibitors would enable patient selection, minimise chances of severe toxicity in those less likely to respond, and may define novel strategies to restore drug sensitivity.

Methods

A high-throughput large-scale RNA interference screen in the HER2-amplified GOC cell line NCI-N87 and the HER2-non-amplified cell line FLO-1 was performed in order to discover novel miRs involved in sensitivity and resistance to trastuzumab. Cells were transfected using a library of 1015 miR mimics, control miRs and siRNAs, and siPLK1 positive control. They were treated 48 hours later with cisplatin + 5FU + trastuzumab based on IC50 data previously obtained. Cell viability was analysed after 72 hrs of continuous drug treatment by fluorescence-based assay (Cell Titer Blue® and EnVision™). Data from 3 biological replicates was analysed and shortlisting of significant hits was based on the concordance among data from different replicates. miRs were considered significant if they caused >40% decrease in cell viability with a t-test p value of

Results

Thirty-two miRs caused >40% decrease in cell viability and were associated with a p value of 40% decrease in cell viability and were associated with a p value of

Conclusions

We identified a panel of miRs associated with GOC resistance to HER2 inhibitors in combination with chemotherapy. Inhibition of these miRs significantly affects GOC cell viability and and restores sensitivity to HER2 inhibitors plus chemotherapy. These miRs require validation with Exiqon miR inhibitors and Nanostring analysis. Translational studies will be conducted in the ST03 HER2 substudy (EUDRACT 2006-000811-12).

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

Cancer Research UK

Disclosure

D. Cunningham: Institution has received research funding from AstraZeneca, Amgen, Celgene, Merck Serono, Sanofi, Merrimack, and Medimmune. All other authors have declared no conflicts of interest.