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Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinib
Michela de Martino1, Dazhong Zhuang2, Tobias Klatte1
1Department of Urology; Comprehensive Cancer Center; Medical University and General Hospital Vienna; Vienna, Austria.
Abstract:
Lapatinib, a dual tyrosine kinase inhibitor of ErbB1 and ErbB2, shows a clinical benefit in a subset of patients with advanced urothelial bladder cancer (UBC). We hypothesized that the corresponding gene, ERBB2, is affected by mutations in a subset of UBC and that these mutations impact ErbB2 function, signaling, UBC proliferation, gene expression, and predict response to lapatinib. We found ERBB2 mutations in 5 of 33 UBC cell lines (15%), all of which were derived from invasive or high grade tumors. Phosphorylation and activation of ErbB2 and its downstream pathways were markedly enhanced in mutated cell lines compared with the ERBB2 wild-type. In addition, the gene expression profile was distinct, specifically for genes encoding for proteins of the extracellular matrix. RT112 cells infected with ERBB2 mutants showed a particular growth pattern ("mini-foci"). Upon treatment with lapatinib, 93% of these "mini-foci" were reversed. The sensitivity to lapatinib was greatest among cell lines with ERBB2 mutations. In conclusion, ERBB2 mutations occur in a subset of UBC and impact proliferation, signaling, gene expression and predict a greater response to lapatinib. If confirmed in the clinical setting, this may lead the way toward personalized treatment of a subset of UBC.
Insights
ERBB2 mutations are found in a subset of urothelial bladder cancer (UBC) and enhance ErbB2 signaling. These mutations predict increased sensitivity to lapatinib, suggesting personalized treatment potential.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lapatinib, a dual tyrosine kinase inhibitor, offers clinical benefit in advanced urothelial bladder cancer (UBC).
- The role of ERBB2 gene mutations in UBC and their impact on lapatinib response is not fully understood.
Purpose of the Study:
- To investigate the presence and functional impact of ERBB2 mutations in UBC.
- To determine if ERBB2 mutations predict response to lapatinib treatment in UBC.
Main Methods:
- Screening of 33 UBC cell lines for ERBB2 mutations.
- Assessing ErbB2 phosphorylation, downstream signaling, and gene expression in mutated vs. wild-type cell lines.
- Evaluating the effect of lapatinib on cell proliferation and "mini-foci" formation in ERBB2-mutated cells.
Main Results:
- ERBB2 mutations were identified in 15% of UBC cell lines, predominantly in invasive or high-grade tumors.
- Mutated cell lines exhibited enhanced ErbB2 phosphorylation, signaling, and distinct gene expression profiles, particularly for extracellular matrix genes.
- Lapatinib treatment reversed "mini-foci" growth in mutated cells, with greatest sensitivity observed in cell lines harboring ERBB2 mutations.
Conclusions:
- ERBB2 mutations are present in a subset of UBC, influencing proliferation, signaling, and gene expression.
- ERBB2 mutations are a predictive biomarker for enhanced response to lapatinib in UBC.
- These findings support the potential for personalized lapatinib therapy in a subset of UBC patients.
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