Human Blood Serum Counteracts EGFR/HER2-Targeted Drug Lapatinib Impact on Squamous Carcinoma SK-BR-3 Cell Growth and Gene Expression

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Nina Shaban^1,2,3,a, Mikhail Raevskiy^4,b, Galina Zakharova^4,c, Victoria Shipunova^1,2,d, Sergey Deyev^2,5,e, Maria Suntsova^3,6,f, Maksim Sorokin^1,6,7,g, Anton Buzdin^1,2,3,4,h, and Dmitri Kamashev^2,3,6,i*

¹Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia

²Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia

³The National Medical Research Center for Endocrinology, 117036 Moscow, Russia

⁴World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, 119991 Moscow, Russia

⁵“Biomarker” Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia

⁶Sechenov First Moscow State Medical University, 119991 Moscow, Russia

⁷PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), 1200 Brussels, Belgium

Received November 10, 2023; Revised January 17, 2024; Accepted February 20, 2024

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Lapatinib is a targeted therapeutic inhibiting HER2 and EGFR proteins. It is used for the therapy of HER2-positive breast cancer, although not all the patients respond to it. Using human blood serum samples from 14 female donors (separately taken or combined), we found that human blood serum dramatically abolishes the lapatinib-mediated inhibition of growth of the human breast squamous carcinoma SK-BR-3 cell line. This antagonism between lapatinib and human serum was associated with cancelation of the drug induced G1/S cell cycle transition arrest. RNA sequencing revealed 308 differentially expressed genes in the presence of lapatinib. Remarkably, when combined with lapatinib, human blood serum showed the capacity of restoring both the rate of cell growth, and the expression of 96.1% of the genes expression of which were altered by the lapatinib treatment alone. Co-administration of EGF with lapatinib also restores the cell growth and cancels alteration of expression of 95.8% of the genes specific to lapatinib treatment of SK-BR-3 cells. Differential gene expression analysis also showed that in the presence of human serum or EGF, lapatinib was unable to inhibit the Toll-Like Receptor signaling pathway and alter expression of genes linked to the Gene Ontology term of Focal adhesion.

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KEY WORDS: EGFR, Erbb2, HER-targeted cancer therapy, human blood serum, lapatinib, EGF, squamous cell carcinoma, SK-BR-3 cells, drug resistance, transcriptome profiling

DOI: 10.1134/S000629792403009X

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