A MET Targeting Antibody-Drug Conjugate Overcomes Gemcitabine Resistance in Pancreatic Cancer.
Animals
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Line, Tumor
Deoxycytidine
/ analogs & derivatives
Drug Resistance, Neoplasm
Humans
Immunoconjugates
/ therapeutic use
Male
Mice
Pancreatic Neoplasms
/ drug therapy
Proto-Oncogene Proteins c-met
/ analysis
Xenograft Model Antitumor Assays
Gemcitabine
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 04 2021
01 04 2021
Historique:
received:
17
08
2020
revised:
16
11
2020
accepted:
08
01
2021
pubmed:
17
1
2021
medline:
11
3
2022
entrez:
16
1
2021
Statut:
ppublish
Résumé
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. 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 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 Together, these results suggest the promise of agents such as TR1801-ADC as a novel approach to the treatment of pancreatic cancer.
Identifiants
pubmed: 33451980
pii: 1078-0432.CCR-20-3210
doi: 10.1158/1078-0432.CCR-20-3210
doi:
Substances chimiques
Immunoconjugates
0
Deoxycytidine
0W860991D6
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Gemcitabine
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2100-2110Subventions
Organisme : NCI NIH HHS
ID : R01 CA155620
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
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