697PPlasmatic CXCL8 is a marker for TGFß-activated kinase 1 (TAK1) activation which may predict resistance to nanoliposomal irinotecan (nal-IRI) in gemcitabine-refractory pancreatic cancer (PC) patients

Abstract Background PC remains one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We recently identified TAK1 as a central hub integrating the most relevant signals sustaining PC chemoresistance. nal-IRI is a novel standard of care for metastatic PC patients who had beenpreviously treated with a gemcitabine-based therapy.We endeavoured to identify circulating markers for TAK1 activation predicting chemoresistance in this clinical setting. Methods In vivo activity of nal-IRI was validated in an orthotopic nude mouse model of PC cells expressing TAK1- specific shRNA or a scramble sequence as control. Using multiplex xMAP/Luminex technology,the samples from 77 metastatic PC patients progressing after gemcitabine and prospectively enrolled to receive nal-IRI + 5FU/LV were analysed for the plasma concentration of 20 different TH1and TH2cytokines.The optimal cut-off thresholds able to significantly predict patient outcome were obtained based on the maximization of the Youden index. Results A significant tumour volume reduction in mice bearing shTAK1 PCtreated with nal-IRIwas detected, whereas controls were resistant to this agent. Differential gene expression profiling revealed CXCL8 as the most significantly downregulated gene coding for secreted proteins in[Office1] shTAK1 PC cell lines. After a 27 month median follow-up, in the overall population the median progression-free survival (PFS) was 3.3 months (95% CI = 3.039-3.561) and the median overall survival (OS) was 7.3 months (95% CI = 5.487-9.113). Cox proportional hazard regression multivariate analysis confirmed CXCL8 as the circulating factor most significantly correlated with survival outcomes. Patients with CXCL8 higher than 16.68 pg/mL cut-off value had a PFS of 2.8 vs 3.4 months (HR = 2.61, 95% CI = 1.42-4.79, p = 0.0014), and an OS of 5.3 vs 8.9 months (HR = 3.7, 95% CI = 1.93-7.11, p = 2.6e-05), respectively. Conclusions We identified CXCL8 as the most significant circulating marker of TAK1 activation. Our study candidates CXCL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory PC patients. Legal entity responsible for the study The authors. Funding Associazione Italiana per la Ricerca sul Cancro (AIRC). Disclosure D. Melisi: Advisory / Consultancy, Research grant / Funding (institution): Shire. All other authors have declared no conflicts of interest.