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Updated: Oct 10, 2025

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1)

Miwa Fujihara1, Tadahiko Shien1, Kazuhiko Shien1

  • 1Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.

International Journal of Molecular Sciences
|December 10, 2021
PubMed

Insights

Trastuzumab-emtansine (T-DM1) resistance in HER2-positive breast cancer is linked to YES1 amplification. Continuous inhibition of YES1 is crucial for overcoming T-DM1 resistance after trastuzumab resistance develops.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Trastuzumab-emtansine (T-DM1) targets HER2-positive metastatic breast cancer (MBC), effective even with trastuzumab resistance.
  • Mechanisms of T-DM1 resistance, especially after prior trastuzumab resistance, are not fully understood.
  • Previous work identified YES1 amplification in trastuzumab-resistant HER2-amplified breast cancer cells.

Purpose of the Study:

  • To investigate the mechanisms of T-DM1 resistance in cells that have acquired resistance to both trastuzumab and T-DM1.
  • To analyze the role of YES1 in the development of dual resistance to trastuzumab and T-DM1.

Main Methods:

  • Establishment of a novel cell line resistant to both trastuzumab and T-DM1.
  • Analysis of YES1 amplification and its correlation with resistance.
  • Gene knockdown of YES1 and treatment with Src inhibitor (dasatinib) to assess sensitivity restoration.

Main Results:

  • Initially, T-DM1 was effective against the YES1-amplified trastuzumab-resistant cell line, but T-DM1 resistance gradually emerged.
  • YES1 amplification further increased in the dual-resistant cell line.
  • YES1 knockdown or dasatinib treatment restored sensitivity to T-DM1.

Conclusions:

  • YES1 is significantly associated with T-DM1 resistance, particularly following acquired trastuzumab resistance.
  • Sustained inhibition of YES1 is a potential strategy to overcome T-DM1 resistance in HER2-positive breast cancer.
Keywords:
T-DM1YES1breast cancerdasatinibdrug resistance

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