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

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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“…The SFK regulates a variety of cellular processes and has an important role in maintaining cellular homeostasis. The unique serine/threonine phosphorylation domain in YES1 regulates cell cycle progression, and this gene has high expression in a variety of tumors, including non-small cell lung cancer ( 40 ), gastric cancer ( 41 ), ovarian cancer ( 42 ), and breast cancer ( 43 ), and is therefore considered a novel therapeutic target and biomarker for cancer ( 44 ). YES1 is associated with several receptor tyrosine kinases (RTKs; EGFR, CSF1R, and SCFR), G protein-coupled receptors (P2RY2 and AT1R), and cytokine receptors (IL11, CD95, and GM-CSF).…”

Emerging Roles of YES1 in Cancer: The Putative Target in Drug Resistance

“…BT-474 cells with HER2 amplification that acquired resistance to trastuzumabemtansine (BT-474-R/TDR) exhibited increased HER2 expression and Akt phosphorylation. The phosphorylation levels of Src, along with YES1 expression, were upregulated in BT-474-R/TDR cells [69]. YES1 knockdown or dasatinib administration is effective even after acquiring resistance to both trastuzumab and T-DM1 [69].…”

“…The phosphorylation levels of Src, along with YES1 expression, were upregulated in BT-474-R/TDR cells [69]. YES1 knockdown or dasatinib administration is effective even after acquiring resistance to both trastuzumab and T-DM1 [69]. Therefore, a promising approach for overcoming resistance to HER2-targeted drugs involves the simultaneous inhibition of both HER2 and YES1.…”

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“…YES, proto-oncogene 1 (YES1) is an important member of the Src family tyrosine kinases (SFKs) and a key regulator of tumor growth (22). The important role of YES1 has also been reported to be involved in human cancer development, including prostate cancer (23).…”