Plasma Interleukin-8 is a biomarker for TAK1 activation and predicts resistance to nanoliposomal irinotecan in patients with gemcitabine-refractory pancreatic cancer.

Purpose: Pancreatic cancer is one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We identified TAK1 as a central hub sustaining this resistance. Nanoliposomal irinotecan (nal-IRI)is a novel treatment for metastatic gemcitabine-refractory pancreatic cancer. We endeavored to identify circulating markers for TAK1 activation predicting chemoresistance in this setting. Experimental design: In vivo activity of nal-IRI was validated in an orthotopic nude murine model expressing TAK1-specific shRNA. Plasma concentration of 20 different cytokines were measured by a multiplex xMAP/Luminex technology in patients prospectively enrolled to receive nal-IRI plus 5-fluorouracil/leucovorin (5-FU/LV). The optimal cutoff thresholds able to significantly predict patients9 outcome were obtained based on the maximization of the Youden9s statistics. Results Differential expression profiling revealed the gene coding for interleukin-8 as the most significantly downregulated in shTAK1 pancreatic cancer cell lines. Mice bearing shTAK1-tumors had significantly lower plasma levels of interleukin-8 and experienced a significant reduction in tumor growth if treated with nal-IRI, while those bearing TAK1-proficient tumors were resistant to this agent. In a discovery cohort of 77 patients, interleukin-8 was the circulating factor most significantly correlated with survival (plasma levels lower vs. higher than cutoff: mPFS 3.4 vs. 2.8 months, HR=2.55, 95%CI=1.39-4.67, P=0.0017; mOS 8.9 vs.5.3 months, HR=3.51, 95%CI=0.84-6.68, P=4.9e-05). These results were confirmed in a validation cohort of 50 patients. Conclusion Our study identified interleukin-8 as the most significant circulating factor for TAK1 pathway activation and candidates interleukin-8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory pancreatic cancer patients.