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An auristatin-based antibody-drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer.

Authors
  • Bourillon, Laura1
  • Bourgier, Céline1, 2
  • Gaborit, Nadège1
  • Garambois, Véronique1
  • Llès, Eva1
  • Zampieri, Alexandre1
  • Ogier, Charline1
  • Jarlier, Marta2
  • Radosevic-Robin, Nina3
  • Orsetti, Béatrice1
  • Delpech, Hélène1
  • Theillet, Charles1
  • Colombo, Pierre-Emmanuel1, 2
  • Azria, David1, 2
  • Pèlegrin, André1
  • Larbouret, Christel1
  • Chardès, Thierry1, 4
  • 1 Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), 34298, Montpellier, France. , (France)
  • 2 Institut Régional du Cancer de Montpellier (ICM), 34298, Montpellier, France. , (France)
  • 3 Department of Biopathology, Jean Perrin Comprehensive Cancer Center and INSERM/UCA UMR 1240, 63011, Clermont-Ferrand, France. , (France)
  • 4 Centre National de la Recherche Scientifique (CNRS), Paris, France. , (France)
Type
Published Article
Journal
International Journal of Cancer
Publisher
Wiley (John Wiley & Sons)
Publication Date
Oct 01, 2019
Volume
145
Issue
7
Pages
1838–1851
Identifiers
DOI: 10.1002/ijc.32273
PMID: 30882895
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the nonligand competing anti-HER3 antibody 9F7-F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7-F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody-drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE-based HER3 antibody-drug conjugate (HER3-ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3-positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3-ADC decreased the clonogenic survival of irradiated cells by increasing DNA double-strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3-ADC favored the inhibition of the AKT-induced survival pathway, together with more efficient caspase 3/PARP-mediated apoptosis. Incubation with HER3-ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3-ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient-derived xenografts, and reduced proliferation (KI67-positive cells). Combining auristatin radiosensitizer delivery via an HER3-ADC with radiotherapy is a new promising therapeutic strategy in PDAC. © 2019 UICC.

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