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: We show that MET is 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.

Overcoming the Tumor Microenvironmental Barriers of Pancreatic Ductal Adenocarcinomas for Achieving Better Treatment Outcomes

“…successfully designed an antibody‐drug conjugate (TR1801‐ADC) that enhanced the tumor inhibition (in vitro and in vivo) in Met overexpressed pancreatic cancer and worked in synergy with gemcitabine. [ 78 ] CSCs are one of the leading players of PDAC distal metastasis. Hermann et al.…”

Multiple Perspectives Reveal the Role of DNA Damage Repair Genes in the Molecular Classification and Prognosis of Pancreatic Adenocarcinoma

“…To facilitate application, five DDR- and immune-based genes were finally selected and DPRS was subsequently constructed. Studies have consistently shown that MET overexpression is a negative prognostic indicator in a variety of malignancies, and activation of the HGF-MET axis was associated with the drug resistance of tumor cells [ 18 , 19 , 20 ]. In this study, MET was significantly negatively correlated with CD8+ T cells, CD4+ T memory activated cells, plasma cells and naïve B cells, respectively.…”

The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy

“…Additionally, a recent preclinical study has identified signaling by the hepatocyte growth factor receptor MET as a potential driver of Gemcitabine resistance in PDAC. In this work, the authors show that MET is highly expressed at the plasma membrane of pancreatic cancer cells, and that TR1801-ADC, a novel antibody drug conjugate composed of a MET antibody conjugated to the highly potent pyrrolobenzodiazepine toxin-linker Tesirin was highly effective in MET-overexpressing patient derived xenografts, and synergized with Gemcitabine, even in tumors previously demonstrated to be resistant to Gemcitabine (183). Hence, these and other combination strategies warrant continued exploration in the treatment of Gemcitabine-refractory PDAC.…”