Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer

• DOI: 10.1007/s10549-010-1090-x
• Publication Date: 2010-08-20T06:43:30Z
• Authors: Teemu T. Junttila; Guangmin Li; Kathryn Parsons; Gail Lewis Phillips; Mark X. Sliwkowski
• Keywords: Immunoconjugates; Cell Survival; Immunotoxins; Blotting, Western; Antibody-Dependent Cell Cytotoxicity; Antibodies, Monoclonal; Mice, Nude; Breast Neoplasms; Lapatinib; Mice, Transgenic; Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; 3. Good health; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; 0302 clinical medicine; Drug Resistance, Neoplasm; Cell Line, Tumor; Animals; Humans; Female; Maytansine

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.