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

Authors
  • Bourillon, Laura
  • Bourgier, Céline
  • Gaborit, Nadège
  • Garambois, Véronique
  • Lles, Eva
  • Zampieri, Alexandre
  • Ogier, Charline
  • Jarlier, Marta
  • Radosevic-Robin, Nina
  • Orsetti, Béatrice
  • Delpech, Hélène
  • Theillet, Charles
  • Colombo, Pierre-Emmanuel
  • Azria, David
  • Pèlegrin, André
  • Larbouret, Christel
  • Chardès, Thierry
Publication Date
Mar 18, 2019
Source
HAL-UPMC
Keywords
Language
English
License
Unknown
External links

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemo- and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the non-ligand 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. This article is protected by copyright. All rights reserved.

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