YES1 amplification confers trastuzumab–emtansine (T-DM1) resistance in HER2-positive cancer
Open Access
- 23 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 123 (6), 1000-1011
- https://doi.org/10.1038/s41416-020-0952-1
Abstract
Background Trastuzumab–emtansine (T-DM1), one of the most potent HER2-targeted drugs, shows impressive efficacy in patients with HER2-positive breast cancers. However, resistance inevitably occurs and becomes a critical clinical problem. Methods We modelled the development of acquired resistance by exposing HER2-positive cells to escalating concentrations of T-DM1. Signalling pathways activation was detected by western blotting, gene expression was analysed by qRT-PCR and gene copy numbers were determined by qPCR. The role of Yes on resistance was confirmed by siRNA-mediated knockdown and stable transfection-mediated overexpression. The in vivo effects were tested in xenograft model. Results We found that Yes is overexpressed in T-DM1–resistant cells owing to amplification of chromosome region 18p11.32, where the YES1 gene resides. Yes activated multiple proliferation-related signalling pathways, including EGFR, PI3K and MAPK, and led to cross-resistance to all types of HER2-targeted drugs, including antibody-drug conjugate, antibody and small molecule inhibitor. The outcome of this cross-resistance may be a clinically incurable condition. Importantly, we found that inhibiting Yes with dasatinib sensitised resistant cells in vitro and in vivo. Conclusions Our study revealed that YES1 amplification conferred resistance to HER2-targeted drugs and suggested the potential application of the strategy of combining HER2 and Yes inhibition in the clinic.Keywords
Funding Information
- National Natural Science Foundation of China (81502636)
- Shanghai Science and Technology Development Foundation (18DZ2293200)
- Yunnan Provincial Science and Technology Department (2017ZF010)
This publication has 53 references indexed in Scilit:
- Dasatinib in previously treated metastatic colorectal cancer: a phase II trial of the University of Chicago Phase II ConsortiumInvestigational New Drugs, 2011
- Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapyEuropean Journal of Cancer, 2010
- Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trialThe Lancet, 2010
- Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancerBreast Cancer Research and Treatment, 2010
- A Phase II Study of Dasatinib in Patients with Chemosensitive Relapsed Small Cell Lung Cancer (Cancer and Leukemia Group B 30602)Journal of Thoracic Oncology, 2010
- LapatinibNature Reviews Drug Discovery, 2007
- Targeting the function of the HER2 oncogene in human cancer therapeuticsOncogene, 2007
- Physical and Functional Interactions between Cas and c-Src Induce Tamoxifen Resistance of Breast Cancer Cells through Pathways Involving Epidermal Growth Factor Receptor and Signal Transducer and Activator of Transcription 5bCancer Research, 2006
- Thymidylate synthase pharmacogeneticsInvestigational New Drugs, 2005
- CELLULAR FUNCTIONS REGULATED BY SRC FAMILY KINASESAnnual Review of Cell and Developmental Biology, 1997