Acetyltanshinone IIA is more potent than lapatinib in inhibiting cell growth and degrading HER2 protein in drug-resistant HER2-positive breast cancer cells

• Published in: Cancer letters 2020-10, Vol.490, p.1-11
• Main Authors: Huang, Bin, Yip, Wai Kien, Wei, Na, Luo, Kathy Qian
• Format: Article
• Language: English
• Subjects: Acetyltanshinone IIA; Animals; Antibodies; Antineoplastic Agents - pharmacology; Binding sites; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; c-Met protein; Cancer therapies; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Degradation; Drug resistance; Drug Resistance, Neoplasm - drug effects; Epidermal growth factor; ErbB-2 protein; Female; Gene amplification; HER2 degradation; HER2-positive breast cancer; Humans; Inhibitor drugs; Insulin-like growth factors; Kinases; Lapatinib - pharmacology; Malignancy; Medical prognosis; Mice; Mice, Nude; Penicillin; Phenanthrenes - pharmacology; Phosphorylation; Proteasomes; Protein-tyrosine kinase; Proteins; Receptor, ErbB-2 - drug effects; Receptor, ErbB-2 - metabolism; Targeted cancer therapy; Ubiquitination; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.06.010

High expression of human epidermal factor receptor 2 (HER2) is directly related to tumor progression, malignancy and drug resistance in HER2-positive breast cancer (HER2-PBC). The major limitation of current anti-HER2 therapies is that they cannot reduce the levels of HER2 protein. Here, we investigated the effect of acetyltanshinone IIA (ATA) in lapatinib-resistant HER2-PBC cells. Our data showed that ATA exhibited more potent effects than lapatinib against drug-resistant HER2-PBC cells in terms of (1) inhibiting cell growth, (2) reducing phosphorylated and total HER2 levels, (3) inhibiting tumor xenograft growth in nude mice, and (4) reducing HER2 protein levels in tumor xenografts. A mechanistic study revealed that ATA promoted HER2 degradation via increasing c-Cbl and CHIP-mediated HER2 ubiquitination and subsequent HER2 degradation by the proteasome or lysosome. ATA also reduced the levels of other tyrosine kinase receptors (TKRs), such as HER3, IGF-1R and MET, in lapatinib-resistant cells. Our findings suggest that direct degradation of HER2 and other TKRs can be an effective strategy for combatting drug resistance. They also indicate the potential utilization of ATA in treating breast cancer that is resistant or nonresponsive to current HER2-targeted therapies. •Current anti-HER2 therapies are not effective in degrading HER2 protein.•ATA inhibited the growth of tumor xenografts in nude mice more potently than lapatinib.•ATA reduced the levels of HER2 protein in HER2+/lapatinib-resistant breast cancer cells.•ATA also reduced the protein levels of HER3, IGF-1R and MET in drug-resistant cells.•ATA can be used to treat breast cancer that is resistant to current HER2-targeted therapies.