preventing/reversing resistance to herceptin

[Lani]

MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells
Journal Breast Cancer Research and Treatment

Issue Volume 118, Number 1 / November, 2009

Pages 113-124

Shawn P. Fessler1, Mark T. Wotkowicz1, Sanjeev K. Mahanta1 and Cynthia Bamdad1

(1) Minerva Biotechnologies, Waltham, MA 02451, USA


Abstract In the United States, 211,000 women are diagnosed each year with breast cancer. Of the 42,000 breast cancer patients who overexpress the HER2 growth factor receptor, <35% are responsive to treatment with the HER2-disabling antibody, called trastuzumab (Herceptin). Despite those statistics, women diagnosed with breast cancer are now tested to determine how much of this important growth factor receptor is present in their tumor because patients whose treatment includes trastuzumab are three-times more likely to survive for at least 5 years and are two-times more likely to survive without a cancer recurrence. Unfortunately, even among the group whose cancers originally respond to trastuzumab, 25% of the metastatic breast cancer patients acquire resistance to trastuzumab within the first year of treatment. Follow-on “salvage” therapies have prolonged life for this group but have not been curative. Thus, it is critically important to understand the mechanisms of trastuzumab resistance and develop therapies that reverse or prevent it. Here, we report that molecular analysis of a cancer cell line that was induced to acquire trastuzumab resistance showed a dramatic increase in the amount of the cleaved form of the MUC1 protein, called MUC1*. We recently reported that MUC1* functions as a growth factor receptor on cancer cells and on embryonic stem cells. Here, we show that treating trastuzumab-resistant cancer cells with a combination of MUC1* antagonists and trastuzumab, reverses the drug resistance. Further, HER2-positive cancer cells that are intrinsically resistant to trastuzumab became trastuzumab-sensitive when treated with MUC1* antagonists and trastuzumab. Additionally, we found that tumor cells that had acquired Herceptin resistance had also acquired resistance to standard chemotherapy agents like Taxol, Doxorubicin, and Cyclophosphamide. Acquired resistance to these standard chemotherapy drugs was also reversed by combined treatment with the original drug plus a MUC1* inhibitor.

[chrisy]

Thanks Lani,

OK, so are there any MUC1 antagonists/inhibitor out there, either naturally or in a form tested beyond a petri dish?

Sounds promising...but not too close to the clinic yet

OK I found some research that had been on nude mice...let's get it on up the food chain!

[SuzEQ]

It's not clear from this paper, or at least to me, if they are lumping newly diagnosed/early stage patients with metastatic patients in their statistics of Herceptin resistance. My understanding is there is a difference and there are other pathways at work in metastatic disease which leads to the resistance that are not operative in early stage disease .