Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells

• Published in: Molecular cancer therapeutics Vol. 17; no. 7; pp. 1441 - 1453
• Main Authors: Li, Guangmin, Guo, Jun, Shen, Ben-Quan, Yadav, Daniela Bumbaca, Sliwkowski, Mark X, Crocker, Lisa M, Lacap, Jennifer A, Phillips, Gail D Lewis
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01-07-2018
• Subjects: 1-Phosphatidylinositol 3-kinase; Animals; ATP Binding Cassette Transporter, Subfamily B - genetics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Bridged-Ring Compounds - pharmacology; Cancer; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; ErbB-2 protein; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunoconjugates - pharmacology; Immunotherapy; Inhibitors; MDR1 protein; Medical treatment; Metastases; Mice; Monoclonal antibodies; Patients; Phosphatidylinositol 3-Kinases - genetics; Protein-tyrosine kinase receptors; PTEN Phosphohydrolase - genetics; PTEN protein; Receptor, ErbB-2 - genetics; Signal transduction; Signal Transduction - drug effects; Targeted cancer therapy; Taxanes; Taxoids - pharmacology; Trastuzumab; Trastuzumab - pharmacology; Tumor cells; Tyrosine; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-17-0296

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the antimitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant
models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and upregulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1-resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1-resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways.
.