YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development |
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| Authors: | Miwa Fujihara Tadahiko Shien Kazuhiko Shien Ken Suzawa Tatsuaki Takeda Yidan Zhu Tomoka Mamori Yusuke Otani Ryo Yoshioka Maya Uno Yoko Suzuki Yuko Abe Minami Hatono Takahiro Tsukioki Yuko Takahashi Mariko Kochi Takayuki Iwamoto Naruto Taira Hiroyoshi Doihara Shinichi Toyooka |
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| Affiliation: | 1.Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; (M.F.); (K.S.); (K.S.); (Y.Z.); (T.M.); (Y.O.); (R.Y.); (M.U.); (Y.S.); (Y.A.); (M.H.); (T.T.); (Y.T.); (M.K.); (T.I.); (N.T.); (H.D.); (S.T.);2.Departments of Pharmacy, Okayama University Hospital, Okayama 700-8558, Japan; |
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| Abstract: | 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 HER2-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 YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 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. |
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| Keywords: | breast cancer YES1 T-DM1 dasatinib drug resistance |
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