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The multitargeted receptor tyrosine kinase inhibitor sunitinib induces resistance of HER2 positive breast cancer cells to trastuzumab-mediated ADCC.
Guti, Eliza; Regdon, Zsolt; Sturniolo, Isotta; Kiss, Alexandra; Kovács, Katalin; Demény, Máté; Szöor, Árpád; Vereb, György; Szöllosi, János; Hegedus, Csaba; Polgár, Zsuzsanna; Virág, László.
Afiliación
  • Guti E; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Regdon Z; Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
  • Sturniolo I; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Kiss A; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Kovács K; Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
  • Demény M; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Szöor Á; Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
  • Vereb G; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Szöllosi J; MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary.
  • Hegedus C; MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary.
  • Polgár Z; Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Virág L; MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary.
Cancer Immunol Immunother ; 71(9): 2151-2168, 2022 Sep.
Article en En | MEDLINE | ID: mdl-35066605
Despite recent advances in the development of novel personalized therapies, breast cancer continues to challenge physicians with resistance to various advanced therapies. The anticancer action of the anti-HER2 antibody, trastuzumab, involves antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells. Here, we report a repurposing screen of 774 clinically used compounds on NK-cell + trastuzumab-induced killing of JIMT-1 breast cancer cells. Using a calcein-based high-content screening (HCS) assay for the image-based quantitation of ADCC that we have developed and optimized for this purpose, we have found that the multitargeted tyrosine kinase inhibitor sunitinib inhibits ADCC in this model. The cytoprotective effect of sunitinib was also confirmed with two other assays (lactate dehydrogenase release, and electric cell substrate impedance sensing, ECIS). The drug suppressed NK cell activation as indicated by reduced granzyme B deposition on to the target cells and inhibition of interferon-γ production by the NK cells. Moreover, sunitinib induced downregulation of HER2 on the target cells' surface, changed the morphology and increased adherence of the target cells. Moreover, sunitinib also triggered the autophagy pathway (speckled LC3b) as an additional potential underlying mechanism of the cytoprotective effect of the drug. Sunitinib-induced ADCC resistance has been confirmed in a 3D tumor model revealing the prevention of apoptotic cell death (Annexin V staining) in JIMT-1 spheroids co-incubated with NK cells and trastuzumab. In summary, our HCS assay may be suitable for the facile identification of ADCC boosting compounds. Our data urge caution concerning potential combinations of ADCC-based immunotherapies and sunitinib.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama Límite: Female / Humans Idioma: En Revista: Cancer Immunol Immunother Asunto de la revista: ALERGIA E IMUNOLOGIA / NEOPLASIAS / TERAPEUTICA Año: 2022 Tipo del documento: Article País de afiliación: Hungria Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama Límite: Female / Humans Idioma: En Revista: Cancer Immunol Immunother Asunto de la revista: ALERGIA E IMUNOLOGIA / NEOPLASIAS / TERAPEUTICA Año: 2022 Tipo del documento: Article País de afiliación: Hungria Pais de publicación: Alemania