Trastuzumab emtansine is active on HER-2 overexpressing NSCLC cell lines and overcomes gefitinib resistance

Abstract

BackgroundHER-2 represents a relatively new therapeutic target for non small cell lung cancer (NSCLC) patients. The incidence for reported HER-2 overexpression/amplification/mutations ranges from 2 to 20% in NSCLC. Moreover, HER-2 amplification is a potential mechanism of resistance to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKI) (about 10% of cases). T-DM1, trastuzumab emtansine is an antibody-drug conjugate composed by the monoclonal antibody trastuzumab and the microtubule polymerization inhibitor DM1. The activity of T-DM1 has been studied in breast cancer but the role of T-DM1 in lung cancer remains unexplored.MethodsAntiproliferative and proapoptotic effects of T-DM1 have been investigated in different NSCLC cell lines by MTT, crystal violet staining, morphological study and Western blotting. HER-2 expression and cell cycle were evaluated by flow cytometry and Western blotting. Antibody dependent cell cytotoxicity (ADCC) was measured with a CytoTox assay. Xenografted mice model has been generated using a NSCLC cell line to evaluate the effect of T-DM1 on tumor growth. Moreover, a morphometric and immunohistochemical analysis of tumor xenografts was conducted.ResultsIn this study we investigated the effect of T-DM1 in a panel of NSCLC cell lines with different HER-2 expression levels, in H1781 cell line carrying HER-2 mutation and in gefitinib resistant HER-2 overexpressing PC9/HER2cl1 cell clone. T-DM1 efficiently inhibited proliferation with arrest in G2-M phase and induced cell death by apoptosis in cells with a significant level of surface expression of HER-2. Antibody-dependent cytotoxicity assay documented that T-DM1 maintained the same activity of trastuzumab. Our data also suggest that targeting HER-2 with T-DM1 potentially overcomes gefitinib resistance. In addition a correlation between cell density/tumor size with both HER-2 expression and T-DM1 activity was established in vitro and in an in vivo xenograft model.ConclusionsOur results indicate that targeting HER-2 with T-DM1 may offer a new therapeutic approach in HER-2 over-expressing lung cancers including those resistant to EGFR TKIs.

Targeting HER2 with T-DM1, an Antibody Cytotoxic Drug Conjugate, is Effective in HER2 Over Expressing Bladder Cancer

“…The effect of T-DM1 is dependent on HER2 expression level, as other reports have suggested. 17,20,25 Similar findings were made in the orthotopic xenograft model. Together these results represent the preclinical proof of principle that T-DM1 warrants further clinical investigation in higher HER2-expressing bladder cancer.…”

“…Mice were treated weekly with 15 mg/kg of each drug as previously reported. 3,4,17 Tumor growth inhibition by T-DM1 was observed one week after first treatment. Xenograft growth was significantly inhibited by T-DM1 compared to treatment with control IgG and trastuzumab (P < 0.01, from day 19 to 29) (Fig.…”

T-DM1, a novel antibody-drug conjugate, is highly effective against uterine and ovarian carcinosarcomas overexpressing HER2

“…The mice were randomized to receive T-DM1 (15 mg/kg), trastuzumab (15 mg/kg), or vehicle sterile water. Drug dosages were chosen accordingly to previous studies conducted on different xenograft models [29–31]. All treatment drugs were given as an intravenous (IV) injection once per week.…”

Complex Structured Fluorescent Polythiophene Graft Copolymer as a Versatile Tool for Imaging, Targeted Delivery of Paclitaxel, and Radiotherapy

“…It has been shown that, expression of HER2/neu may also be increased in lung cancer 16,17 . It functions as an enhancer of proliferative and anti-apoptotic signals which play an important role in cancer cell survival 18 .…”