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.
Highlights
The phase III EMILIA study [3] evaluated the safety and efficacy of T-DM1 compared with lapatinib plus capecitabine for human epidermal growth factor receptor 2 (HER2)-positive patients with locally advanced breast cancer and metastatic breast cancer (MBC) previously treated with trastuzumab and a taxane agent
≥grade 3 adverse events were lower with T-DM1 than with lapatinib plus capecitabine
HER2-positive MBC that has become resistant to trastuzumab or T-DM1, but this drug is associated with severe adverse events, such as interstitial pneumonia
Summary
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for approximately 20% of malignant breast tumors [1]. HER2-positive breast cancer patients used to have poor outcomes, but the recent development of novel drugs based on molecular-targeting mechanisms have improved outcomes for patients with this type of breast cancer. Trastuzumab-emtansine (T-DM1), an antibody-drug conjugate (ADC), is comprised of the humanized, monoclonal, anti-HER2 antibody trastuzumab conjugated via a non-cleavable linker to the anti-microtubule maytansinoid drug emtansine (DM1) [2]. T-DM1 was approved for HER2-positive metastatic breast cancer (MBC) based on the phase
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