High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer

Abstract

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive subtype of this disease. Targeted treatment has improved outcome, but there is still a need for new therapeutic strategies as some patients respond poorly to treatment. Our aim was to identify compounds that substantially affect viability in HER2+ breast cancer cells in response to combinatorial treatment. We performed a high-throughput drug screen of 278 compounds in combination with trastuzumab and lapatinib using two HER2+ breast cancer cell lines (KPL4 and SUM190PT). The most promising drugs were validated in vitro and in vivo, and downstream molecular changes of the treatments were analyzed. The screen revealed multiple drugs that could be used in combination with lapatinib and/or trastuzumab. The Src-inhibitor dasatinib showed the largest combinatorial effect together with lapatinib in the KPL4 cell line compared to treatment with dasatinib alone (p < 0.01). In vivo, only lapatinib significantly reduced tumor growth (p < 0.05), whereas dasatinib alone, or in combination with lapatinib, did not show significant effects. Protein analyses of the treated xenografts showed significant alterations in protein levels compared to untreated controls, suggesting that all drugs reached the tumor and exerted a measurable effect. In silico analyses suggested activation of apoptosis and reduced activity of survival pathways by all treatments, but the opposite pattern was observed for the combinatorial treatment compared to lapatinib alone.

Targeting HER2-positive breast cancer cells by a combination of dasatinib and BMS-202: Insight into the molecular pathways

“…Today, combination therapy approaches are emerging in the field of cancer management. DA was identified as a potential candidate for combination therapy in HER2positive breast cancer by high-throughput screening [55]. The efficacy of DA as a part of combination therapy against HER2-positive breast cancer was shown in-vitro and in-vivo [35,[56][57][58].…”

A Multi-Drug Concentration Gradient Mixing Chip: A Novel Platform for High-Throughput Drug Combination Screening

“…However, screening drug combinations and determining their appropriate concentrations are time-consuming and costly, and can take over 10 years and cost billions of dollars. Therefore, the development of technologies, including highthroughput screening methods [4][5][6][7], computational modeling [8][9][10], and microfluidic devices [11][12][13], is in high demand.…”