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

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).

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

More exciting news on T-DM1. I just wish they would hurry up and approve T-DM1 for those of us that need it.

Thanks for sharing this news Lani!

Chelee

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

Lani,
This is exciting news. when I went to Memorial Sloan for a 2nd opinion, the oncologist mentioned this as a possibility for brain mets (he's not convinced that it doesn't x the bbb). I sure do wish it is true.

Kris....

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

Thats what i want to find out. Does T-DM1 cross the blood brain barrier. Does anyone out there know?

I have to wait another 4 weeks for my brain MRI and I'll find out what further treatment is needed.

Thanks for the post Lani.

Regards Jacqui

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

Kris, my onc believes it's possible too. He's in the camp that believes the bbb is much more "leaky" than other camps of oncs and researchers have professed over the years. He thinks T-DM1 will help treat my brain.

Jaqui, I don't think we are there yet to know for sure. Have you talked to your onc about starting Tykerb/Xeloda?

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

Lani -

This is incredible news. You are such a blessing to us!

- Kim

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

This is really great news for all of us.

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

Thanks Lani
You always post news that cheers us up!
I agree with Chelee, the sooner you girls get it in the States the sooner we have a chance of getting it across the pond!!

Ellie

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

Interesting phrase - especially when applied to a cancer cell!!!!!