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Significance This study demonstrates the therapeutic efficacy of ceramide-conjugated nanoparticles (PPP-CNP) in trastuzumab-resistant human epidermal growth factor receptor 2-positive (HER2+) breast cancer. The shedding/loss of the HER2 extracellular domain plays… Click to show full abstract
Significance This study demonstrates the therapeutic efficacy of ceramide-conjugated nanoparticles (PPP-CNP) in trastuzumab-resistant human epidermal growth factor receptor 2-positive (HER2+) breast cancer. The shedding/loss of the HER2 extracellular domain plays a significant role in trastuzumab resistance in HER2+ breast cancer. We hypothesized that targeting molecule(s) downstream of HER2 could overcome resistance and promote an anti-tumor effect. Indeed, targeting HER2 downstream target, mixed lineage kinase 3 (MLK3), using a nanoparticle conjugated with the agonist of MLK3, ceramide (PPP-CNP), did induce apoptosis in TR HER2+ breast cancer via upregulation of CD70 protein expression. The PPP-CNP induced cell death in TR cell lines, patient-derived organoids, and xenograft suggesting that PPP-CNP can serve as an alternative agent to overcome trastuzumab resistance in HER2+ breast cancer.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2022
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