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001-es BibID:	BIBFORM100193
035-os BibID:	(Scopus)85123488729 (WOS)000745777900001
Első szerző:	Guti Eliza (Molekuláris biológus)
Cím:	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, Szöőr Árpád, Vereb György, Szöllősi János, Hegedűs Csaba, Polgár Zsuzsanna, Virág László
Dátum:	2022
ISSN:	0340-7004
Megjegyzések:	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 calceinbased 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-? 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.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Sunitinib Natural killer cell Breast cancer ADCC Trastuzumab Herceptin
Megjelenés:	Cancer Immunology Immunotherapy. - 71 : 9 (2022), p. 2151-2168. -
További szerzők:	Regdon Zsolt (1988-) (biokémikus, molekuláris biológus) Sturniolo, Isotta (1994-) Kiss Alexandra (1991-) (klinikai laboratóriumi kutató) Kovács Katalin (1978-) (biokémikus) Demény Máté Ágoston (1976-) (molekuláris biológus) Szöőr Árpád (1984-) (orvos) Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus) Hegedűs Csaba (1980-) (biokémikus, molekuláris biológus) Polgár Zsuzsanna (1978-) (agrármérnök, biotechnológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus)
Pályázati támogatás:	GINOP-2.3.3-15-2016-00020 GINOP GINOP-2.3.2-15-2016-00048 GINOP K132193 OTKA K119690 OTKA
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