PO-501 Deconstructing the role of CD44 in gastric cancer resistance to cisplatin

Introduction Gastric cancer (GC) is the 3rd leading cause of cancer related deaths and the 5th commonest cancer worldwide, affecting ~1 million individuals per year. For early-stage disease, surgical resection is potentially curative, however >80% of GC patients present advanced, unresectable and not curable disease, and an average overall survival (OS) of ~1 year. Poor patient survival is justified by late stage diagnosis and by poor response to therapy. We hypothesised that some GC clones that intrinsically resist to chemotherapy overexpress a variant of CD44, the main cell surface receptor for hyaluronic acid. Supporting this hypothesis is our finding that CD44v6 becomes overexpressed in ~70% of all GCs, as opposed to normal mucosa. Here, we aim to investigate whether CD44v6 overexpression influences response to cisplatin treatment. Material and methods We established isogenic GC cell lines overexpressing either CD44v6, CD44std or an empty vector (Mock), and CD44v6 RNAi-depleted GC cell lines that endogenously express CD44v6. These were all characterised by RT-PCR, western-blot, immunofluorescence and flow-cytometry. The effect of cisplatin on cell survival was evaluated by SRB and Annexin-V assays. The expression of signalling partners downstream of CD44 was evaluated by western-blot and immunofluorescence. Results and discussions CD44v6 overexpression increased cisplatin resistance and its depletion sensitised cells to cisplatin treatment. Moreover, when isogenic CD44v6-expressing cells were co-cultured with the non-expressing counterpart, treated with cisplatin and allowed to recover for 15 days, CD44v6-expressing cells survived, while CD44v6-negative cells were reduced to Conclusion In conclusion, our findings highlight CD44v6 as a modulator of cisplatin resistance in GC that may contribute to the poor therapeutic response in this disease. Novel therapeutic strategies that include CD44v6 depletion at the tumour site, may improve therapy response and survival in GC patients.