A MET targeting antibody-drug conjugate overcomes gemcitabine resistance in pancreatic cancer

Abstract

Purpose: Pancreatic cancer is an aggressive disease associated with a poor 5-year overall survival. Most patients are ineligible for surgery due to late diagnosis and are treated primarily with chemotherapy with very limited success. Pancreatic cancer is relatively insensitive to chemotherapy due to multiple factors, including reduced bioavailability of drugs to tumor cells. One strategy to improve drug efficacy with reduced toxicity is the development of antibody-drug conjugates (ADC), which have now been used successfully to treat both solid and liquid tumors. Here, we evaluate the efficacy of TR1801-ADC, a newly developed ADC composed of a MET antibody conjugated to the highly potent pyrrolobenzodiazepine toxin-linker, tesirine. Experimental Design: We first evaluated MET expression and subcellular localization in pancreatic cancer cell lines, human tumors, and patient-derived xenografts (PDX). We then tested TR1801-ADC efficacy in vitro in pancreatic cancer cell lines. Preclinical evaluation of TR1801-ADC efficacy was conducted on PDXs selected on the basis of their MET expression level. Results:Weshow that METis highly expressed and located at the plasma membrane of pancreatic cancer cells. We found that TR1801-ADC induces a specific cytotoxicity in pancreatic cancer cell lines and a profound tumor growth inhibition, even in a gemcitabine-resistant tumor. We also noted synergism between TR1801-ADC and gemcitabine in vitro and an improved response to the combination in vivo. Conclusions: Together, these results suggest the promise of agents such as TR1801-ADC as a novel approach to the treatment of pancreatic cancer.