Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer

Lixin Zhang, Jason A. Ngo, Michael D. Wetzel, Dario Marchetti

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Heparanase (HPSE) is the dominant mammalian endoglycosidase and important tumorigenic, angiogenic, and pro-metastatic molecule. Highest levels of HPSE activity have been consistently detected in cells possessing highest propensities to colonize the brain, emphasizing the therapeutic potential for targeting HPSE in brain metastatic breast cancer (BMBC). Lapatinib (Tykerb) is a small-molecule and dual inhibitor of human epidermal growth factor receptor1 and 2 (EGFR and HER2, respectively) which are both high-risk predictors of BMBC. It was approved by the US Food and Drug Administration for treatment of patients with advanced or metastatic breast cancer. However, its role is limited in BMBC whose response rates to lapatinib are significantly lower than those for extracranial metastasis. Because HPSE can affect EGFR phosphorylation, we examined Roneparstat, a non-anticoagulant heparin with potent anti-HPSE activity, to inhibit EGFR signaling pathways and BMBC onset using lapatinib-resistant clones generated from HER2-transfected, EGFR-expressing MDA-MB-231BR cells. Cell growth, EGFR pathways, and HPSE targets were assessed among selected clones in the absence or presence of Roneparstat and/or lapatinib. Roneparstat overcame lapatinib resistance by inhibiting pathways associated with EGFR tyrosine residues that are not targeted by lapatinib. Roneparstat inhibited the growth and BMBC abilities of lapatinib-resistant clones. A molecular mechanism was identified by which HPSE mediates an alternative survival pathway in lapatinib-resistant clones and is modulated by Roneparstat. These results demonstrate that the inhibition of HPSE-mediated signaling plays important roles in lapatinib resistance, and provide mechanistic insights to validate the use of Roneparstat for novel BMBC therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)101-113
Number of pages13
JournalNeoplasia (United States)
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • Animals
  • Antineoplastic Agents
  • Brain Neoplasms
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Extracellular Signal-Regulated MAP Kinases
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases
  • Gene Expression
  • Gene Knockdown Techniques
  • Glucuronidase
  • Humans
  • Protein Kinase Inhibitors
  • Quinazolines
  • Receptor, Epidermal Growth Factor
  • Receptor, ErbB-2
  • Signal Transduction
  • Transfection
  • Tumor Burden
  • Xenograft Model Antitumor Assays

ASJC Scopus subject areas

  • Medicine(all)

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