title: Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer.
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.
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Ngo
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wetzel
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030; Department of Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Electronic address: marchett@bcm.edu.
authors.forename: Dario
authors.initials: D
authors.lastname: Marchetti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099175:Heparanase
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005966:Glucuronidase; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000099175:Heparanase