YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development

• Published in: International journal of molecular sciences 2021-11, Vol.22 (23), p.12809
• Main Authors: Fujihara, Miwa, Shien, Tadahiko, Shien, Kazuhiko, Suzawa, Ken, Takeda, Tatsuaki, Zhu, Yidan, Mamori, Tomoka, Otani, Yusuke, Yoshioka, Ryo, Uno, Maya, Suzuki, Yoko, Abe, Yuko, Hatono, Minami, Tsukioki, Takahiro, Takahashi, Yuko, Kochi, Mariko, Iwamoto, Takayuki, Taira, Naruto, Doihara, Hiroyoshi, Toyooka, Shinichi
• Format: Article
• Language: English
• Subjects: Ado-Trastuzumab Emtansine - pharmacology; Antibodies; Antineoplastic Agents, Immunological - pharmacology; Apoptosis; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer therapies; Cell Proliferation; Chemical compounds; dasatinib; Dasatinib - pharmacology; drug resistance; Drug Resistance, Neoplasm - drug effects; Epidermal growth factor; ErbB-2 protein; Female; Growth factors; Humans; Kinases; Metastases; Metastasis; Monoclonal antibodies; Pharmacology; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-yes - antagonists & inhibitors; Proto-Oncogene Proteins c-yes - genetics; Receptor, ErbB-2 - metabolism; RNA, Small Interfering - genetics; T-DM1; Targeted cancer therapy; Trastuzumab; Tumor Cells, Cultured; YES1
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222312809

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in -amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the -amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.