TDM-1 works (on cell lines) even if already resistant to herceptin/lapatinib!!

[Lani]

Trastuzumab-DM1 causes tumor growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo
Mark Barok , Minna Tanner , Katri Koninki and Jorma Isola

Breast Cancer Research 2011, 13:R46doi:10.1186/bcr2868

Published: 21 April 2011
Abstract (provisional)

Introduction
Trastuzumab is widely used for the treatment of HER2-positive breast cancer. Despite encouraging clinical results, a significant fraction of patients are, or become refractory to, the drug. To overcome this, trastuzumab DM1 (T-DM1), a newer, more potent drug has been introduced. We tested the efficacy and mechanisms of action of T-DM1 in nine HER2-positive breast cancer cell lines in vitro and in vivo. The nine cell lines studied included UACC-893, MDA-453 and JIMT-1, which are resistant to both trastuzumab and lapatinib.

Methods
AlamarBlue cell-proliferation assay was used to determine the growth response of breast cancer cell lines to trastuzumab and T-DM1 in vitro. Trastuzumab- and T-DM1-mediated antibody-dependent cellular cytotoxicity (ADCC) was analysed by measuring the lactate dehydrogenase released from the cancer cells as a result of ADCC activity of peripheral blood mononuclear cells. Severe Combined Immunodeficient (SCID) mice were inoculated with trastuzumab-resistant JIMT-1 cells to investigate the tumour inhibitory effect of T-DM1 in vivo. The xenograft samples were investigated using histology and immunohistochemistry.

Results
T-DM1 was strongly growth inhibitory on all investigated HER2-positive breast cancer cell lines in vitro. T-DM1 also evoked antibody-dependent cellular cytotoxicity (ADCC) similar to that of trastuzumab. Outgrowth of JIMT-1 xenograft tumors in SCID mice was significantly inhibited by T DM1. Histologically, the cellular response to T-DM1 consisted of apoptosis and mitotic catastrophe, the latter evidenced by increased number of cells with aberrant mitotic figures and giant multinucleated cells.

Conclusions
Our results suggest mitotic catastrophe as a previously undescribed mechanism of action of T-DM1. T DM1 was found effective even on breast cancer cell lines with moderate HER2 expression levels and cross-resistance to trastuzumab and lapatinib (MDA-453 and JIMT-1).