Cellular and Molecular Biology

YES1 amplification confers trastuzumab–emtansine (T-DM1) resistance in HER2-positive cancer

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.

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Fig. 1: BT-474/R1-7 cells are resistant to HER2-targeted drugs.
Fig. 2: SFK plays a critical role in mediating resistance in BT-474/R1-7 cells.
Fig. 3: Yes is responsible for aberrant activation of signalling pathways in BT-474/R1-7 cells.
Fig. 4: Chromosome region 18p11.32 is amplified in BT-474/R1-7 cells.
Fig. 5: Ectopic expression of Yes confers T-DM1 resistance.
Fig. 6: Yes inhibition overcomes T-DM1 resistance in vivo.

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Authors

Contributions

L.W., H.Q. and L.L. conceived and designed the study; L.W., Q.W. and P.X. developed the methodologies and acquired the data; L.F., Y.L. and H.F. performed in vivo experiments; L.W. and L.L. wrote and revised the paper. All authors read and approved the final paper.

Corresponding authors

Correspondence to Haitian Quan or Liguang Lou.

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Ethics approval and consent to participate

Animal studies were carried out in accordance with guidelines of the Institutional Animal Care and Use Committee at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. The human BT-474 and SK-OV-3 cell lines were obtained from the American Type Culture Collection (Manassas, VA, USA).

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The data generated during the current study are available from the corresponding author upon reasonable request.

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The authors declare no competing interests.

Funding information

This work was supported by National Natural Science Foundation of China (№ 81502636); the Shanghai Science and Technology Committee (№ 18DZ2293200); and the Yunnan Provincial Science and Technology Department (№ 2017ZF010).

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Wang, L., Wang, Q., Xu, P. et al. YES1 amplification confers trastuzumab–emtansine (T-DM1) resistance in HER2-positive cancer. Br J Cancer 123, 1000–1011 (2020). https://doi.org/10.1038/s41416-020-0952-1

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