Therapeutic siRNA for drug-resistant HER2-positive breast cancer

Shenda Gu, Zhi Hu, Worapol Ngamcherdtrakul, David J. Castro, Jingga Morry, Moataz M. Reda, Joe W. Gray, Wassana Yantasee

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

HER2 is overexpressed in about 20% of breast cancers and contributes to poor prognosis. Unfortunately, a large fraction of patients have primary or acquired resistance to the HER2-targeted therapy trastuzumab, thus a multi-drug combination is utilized in the clinic, putting significant burden on patients. We systematically identified an optimal HER2 siRNA from 76 potential sequences and demonstrated its utility in overcoming intrinsic and acquired resistance to trastuzumab and lapatinib in 18 HER2-positive cancer cell lines. We provided evidence that the drug-resistant cancer maintains dependence on HER2 for survival. Importantly, cell lines did not readily develop resistance following extended treatment with HER2 siRNA. Using our recently developed nanoparticle platform, systemic delivery of HER2 siRNA to trastuzumab-resistant tumors resulted in significant growth inhibition. Moreover, the optimal HER2 siRNA could also silence an exon 16 skipped HER2 splice variant reported to be highly oncogenic and linked to trastuzumab resistance.

Original languageEnglish (US)
Pages (from-to)14727-14741
Number of pages15
JournalOncotarget
Volume7
Issue number12
DOIs
StatePublished - Mar 22 2016

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Keywords

  • Breast cancer
  • Her2
  • Nanoparticles
  • SiRNA
  • Trastuzumab resistance

ASJC Scopus subject areas

  • Oncology

Cite this

Gu, S., Hu, Z., Ngamcherdtrakul, W., Castro, D. J., Morry, J., Reda, M. M., Gray, J. W., & Yantasee, W. (2016). Therapeutic siRNA for drug-resistant HER2-positive breast cancer. Oncotarget, 7(12), 14727-14741. https://doi.org/10.18632/oncotarget.7409