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Human Blood Serum Counteracts EGFR/HER2-Targeted Drug Lapatinib Impact on Squamous Carcinoma SK-BR-3 Cell Growth and
Nina Shaban1,2,3, Mikhail Raevskiy4, Galina Zakharova5
1Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia. shaban.na@phystech.edu.
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 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.
Insights
Human blood serum significantly reduces lapatinib
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Lapatinib is a targeted therapy for HER2-positive breast cancer, but patient response varies.
- Understanding factors influencing lapatinib efficacy is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate the effect of human blood serum on lapatinib's efficacy in HER2-positive breast cancer cells.
- To explore the molecular mechanisms underlying serum-mediated antagonism of lapatinib.
Main Methods:
- Utilized human blood serum from 14 female donors with SK-BR-3 breast cancer cells.
- Assessed cell growth inhibition and cell cycle progression.
- Performed RNA sequencing to analyze gene expression changes.
Main Results:
- Human blood serum abolished lapatinib's growth inhibition and reversed G1/S cell cycle arrest in SK-BR-3 cells.
- Serum restored 96.1% of lapatinib-altered gene expression, including key pathways like Toll-Like Receptor signaling and Focal adhesion.
- Epidermal Growth Factor (EGF) mimicked serum's effect, restoring cell growth and gene expression.
Conclusions:
- Human blood serum antagonizes lapatinib's therapeutic effect by counteracting its impact on cell cycle and gene expression.
- EGF may play a role in serum-mediated resistance to lapatinib.
- Further research is needed to elucidate the precise mechanisms and clinical implications.
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