English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

Trastuzumab emtansine (T‐ DM 1), an antibody–drug conjugate ( ADC ) consisting of human epidermal growth factor receptor 2 ( HER 2)‐targeted  mA b trastuzumab linked to antimicrotubule agent mertansine ( DM 1), has been approved for the treatment of  HER 2‐positive metastatic breast cancer. Acquired resistance has been a major obstacle to T‐ DM 1 treatment, and mechanisms remain incompletely understood. In the present study, we established a T‐ DM 1‐resistant N87‐ KR  cell line from  HER 2‐positive N87 gastric cancer cells to investigate mechanisms of acquired resistance and develop strategies for overcoming it. Although the kinetics of binding, internalization, and externalization of T‐ DM 1 were the same in N87‐ KR  cells and N87 cells, N87‐ KR  was strongly resistant to T‐ DM 1, but remained sensitive to both trastuzumab and  DM 1. T‐ DM 1 failed to inhibit microtubule polymerization in N87‐ KR  cells. Consistently, lysine‐ MCC ‐ DM 1, the active T‐ DM 1 metabolite that inhibits microtubule polymerization, accumulated much less in N87‐ KR  cells than in N87 cells. Furthermore, lysosome acidification, achieved by vacuolar H + ‐ ATP ase (V‐ ATP ase), was much diminished in N87‐ KR  cells. Notably, treatment of sensitive N87 cells with the V‐ ATP ase selective inhibitor bafilomycin A1 induced T‐ DM 1 resistance, suggesting that aberrant V‐ ATP ase activity decreases T‐ DM 1 metabolism, leading to T‐ DM 1 resistance in N87‐ KR  cells. Interestingly,  HER 2‐targeted  ADC s containing a protease‐cleavable linker, such as hertuzumab‐vc‐monomethyl auristatin E, were capable of efficiently overcoming this resistance. Our results show for the first time that a decrease in T‐ DM 1 metabolites induced by aberrant V‐ ATP ase activity contributes to T‐ DM 1 resistance, which could be overcome by  HER 2‐targeted  ADC s containing different linkers, including a protease‐cleavable linker. Accordingly, we propose that V‐ ATP ase activity in lysosomes is a novel biomarker for predicting T‐ DM 1 resistance.

Aberrant intracellular metabolism of T‐ DM 1 confers T‐ DM 1 resistance in human epidermal growth factor receptor 2‐positive gastric cancer cells