Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer.
Trastuzumab (Herceptin(®)) is currently used as a treatment for patients whose breast tumors overexpress HER2/ErbB2. Trastuzumab-DM1 (T-DM1, trastuzumab emtansine) is designed to combine the clinical benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine derivative). Currently T-DM1 is being tested in multiple clinical trials. The mechanisms of action for trastuzumab include inhibition of PI3K/AKT signaling pathway, inhibition of HER-2 shedding and Fcγ receptor mediated engagement of immune cells, which may result in antibody-dependent cellular cytotoxicity (ADCC). Here we report that T-DM1 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors.
Junttila
Teemu T
TT
Research Oncology, Genentech, Inc., 1 DNA Way, Mailstop 72, South San Francisco, CA 94080, USA.
Li
Guangmin
G
Parsons
Kathryn
K
Phillips
Gail Lewis
GL
Sliwkowski
Mark X
MX
D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D000922:Immunotoxins / Q000627:therapeutic use*; D000077341:Lapatinib; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011799:Quinazolines / Q000009:adverse effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab
D000080044:Ado-Trastuzumab Emtansine; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D000922:Immunotoxins; D000077341:Lapatinib; D008453:Maytansine; D019869:Phosphatidylinositol 3-Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human