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

Abstract

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 on it. Using human blood serum samples from 14 female donors (separately taken or combined), we found that human blood serum dramatically abolishes lapatinib inhibition of growth of human breast squamous carcinoma SK-BR-3 cell line. This antagonism between lapatinib and human serum was connected with cancel of 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 genes that were altered by lapatinib treatment alone. EGF co-administration with lapatinib also restores the cell growth and cancels alteration of 95.8% of 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 Toll Like Receptor signaling pathway and alter expression of genes linked with Gene Ontology term of Focal adhesion.