Plasma IL8 Is a Biomarker for TAK1 Activation and Predicts Resistance to Nanoliposomal Irinotecan in Patients with Gemcitabine-Refractory Pancreatic Cancer.

Abstract

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 patients' outcome were obtained on the basis of the maximization of the Youden's statistics.

RESULTS:

Differential expression profiling revealed the gene coding for IL8 as the most significantly downregulated in shTAK1 pancreatic cancer cell lines. Mice bearing shTAK1 tumors had significantly lower plasma levels of IL8 and experienced a significant reduction in tumor growth if treated with nal-IRI, whereas those bearing TAK1-proficient tumors were resistant to this agent. In a discovery cohort of 77 patients, IL8 was the circulating factor most significantly correlated with survival (plasma levels lower vs higher than cutoff: mPFS 3.4 months vs 2.8 months; hazard ratio [HR], 2.55; 95% CI, 1.39-4.67; P = 0.0017; median overall survival 8.9 months 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.

CONCLUSIONS:

Our study identified IL8 as the most significant circulating factor for TAK1 pathway activation and candidates IL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory patients with pancreatic cancer.

• Authors: Valeria Merz, Camilla Zecchetto, Raffaela Santoro, Francesca Simionato, Fabio Sabbadini, Domenico Mangiameli, Geny Piro, Alessandro Cavaliere, Michela Deiana, Maria Teresa Valenti, Diana Bazan, Vita Fedele, Sara Lonardi, Davide Melisi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 17 Pg. 4661-4669 (09 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32532788 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• CXCL8 protein, human
• Interleukin-8
• Deoxycytidine
• Irinotecan
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• Gemcitabine

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Biomarkers, Tumor (blood)
• Cell Line, Tumor
• Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Interleukin-8 (blood)
• Irinotecan (pharmacology, therapeutic use)
• MAP Kinase Kinase Kinases (genetics, metabolism)
• Male
• Mice
• Middle Aged
• Pancreatic Neoplasms (blood, drug therapy, genetics)
• Prospective Studies
• Response Evaluation Criteria in Solid Tumors
• Transcriptional Activation
• Xenograft Model Antitumor Assays
• Gemcitabine