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001-es BibID:	BIBFORM121780
035-os BibID:	(Scopus)85195863862
Első szerző:	Ujlaky-Nagy László (biofizikus)
Cím:	Disrupting EGFR-HER2 Transactivation by Pertuzumab in HER2-Positive Cancer : quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome / László Ujlaky-Nagy, János Szöllősi, György Vereb
Dátum:	2024
ISSN:	1422-0067
Megjegyzések:	Pertuzumab (Perjeta?), a humanized antibody binding to the dimerization arm of HER2 (Human epidermal growth factor receptor-2), has failed as a monotherapy agent in HER2 overexpressing malignancies. Since the molecular interaction of HER2 with ligand-bound EGFR (epidermal growth factor receptor) has been implied in mitogenic signaling and malignant proliferation, we hypothesized that this interaction, rather than HER2 expression and oligomerization alone, could be a potential molecular target and predictor of the efficacy of pertuzumab treatment. Therefore, we investigated static and dynamic interactions between HER2 and EGFR molecules upon EGF stimulus in the presence and absence of pertuzumab in HER2+ EGFR+ SK-BR-3 breast tumor cells using Förster resonance energy transfer (FRET) microscopy and fluorescence correlation and cross-correlation spectroscopy (FCS/FCCS). The consequential activation of signaling and changes in cell proliferation were measured by Western blotting and MTT assay. The autocorrelation functions of HER2 diffusion were best fitted by a three-component model corrected for triplet formation, and among these components the slowly diffusing membrane component revealed aggregation induced by EGFR ligand binding, as evidenced by photon-counting histograms and co-diffusing fractions. This aggregation has efficiently been prevented by pertuzumab treatment, which also inhibited the post-stimulus interaction of EGFR and HER2, as monitored by changes in FRET efficiency. Overall, the data demonstrated that pertuzumab, by hindering post-stimulus interaction between EGFR and HER2, inhibits EGFR-evoked HER2 aggregation and phosphorylation and leads to a dose-dependent decrease in cell proliferation, particularly when higher amounts of EGF are present. Consequently, we propose that EGFR expression on HER2-positive tumors could be taken into consideration as a potential biomarker when predicting the outcome of pertuzumab treatment.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk targeted antibody therapy trastuzumab (Herceptin, TrazimeraTM) pertuzumab (Perjeta) Förster resonance energy transfer (FRET) confocal microscopy fluorescence cross-correlation spectroscopy (FCCS) FCS fluorescence correlation spectroscop ErbB2 HER2 EGFR epidermal growth factor receptor
Megjelenés:	International Journal Of Molecular Sciences. - 25 : 11 (2024), p. 1-20. -
További szerzők:	Szöllősi János (1953-) (biofizikus) Vereb György (1965-) (biofizikus, orvos)
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