Lipid-conjugated telomerase template antagonists sensitize resistant HER2-positive breast cancer cells to trastuzumab.
HER2 amplification in breast cancer is associated with a more aggressive disease, greater likelihood of recurrence, and decreased survival compared to women with HER2-negative breast cancer. Trastuzumab is a monoclonal antibody that inhibits HER2 activity, making this compound an important therapeutic option for patients with HER2-positive breast cancer. However, resistance to trastuzumab develops rapidly in a large number of breast cancer patients. The objective of this study was to determine whether GRN163L, a telomerase template antagonist currently in clinical trials for cancer treatment, can augment the effects of trastuzumab in breast cancer cells with HER2 amplification. GRN163L was effective in inhibiting telomerase activity and shortening telomeres in HER2-positive breast cancer cells. We show that GRN163L acts synergistically with trastuzumab in inhibiting HER2-positive breast cancer cell growth. More importantly, we show that GRN163L can restore the sensitivity of therapeutic-resistant breast cancer cells to trastuzumab. These findings implicate that telomerase template antagonists have potential use in the treatment of cancers that have developed resistance to traditional cancer therapy.
Goldblatt
Erin M
EM
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202-5251, USA.
Erickson
Priscilla A
PA
Gentry
Erin R
ER
Gryaznov
Sergei M
SM
Herbert
Brittney-Shea
BS
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009841:Oligonucleotides / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012313:RNA / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D009841:Oligonucleotides; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D012313:RNA; D018719:Erb-b2 Receptor Tyrosine Kinases; D019098:Telomerase; D000068878:Trastuzumab; C546579:5'-oleic-TAGGGTTAGACAA-3'; C505952:GRN163L peptide; C422952:telomerase RNA; C508053:ERBB2 protein, human