open access article Osbourne/Schiff on blocking the her family+ER (H+T+ fulvestrant)

[Lani]

from the same people who brought you the cure of her2+ breast cancer in mice with multiher treatment+/- antiEstrogen treatment, here is the latest work done on cell lines showing what happens with resistance to herceptin, resistance to lapatinib and resistance to the combo and what to do about it

Still in cell lines, but getting closer to clinical trials (like the pertuzumab+herceptin+ taxane trial reported at SABCS)

Hopefully will eventually lead to nonchemo containing trials


Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers - role of estrogen receptor and HER2 reactivation
Yen-Chao Wang, Gladys Morrison, Ryan Gillihan, Jun Guo, Robin M Ward, Xiaoyong Fu, Maria F Botero, Nuala A Healy, Susan G Hilsenbeck, Gail L Phillips, Gary C Chamness, Mothaffar F Rimawi, C Kent Osborne and Rachel Schiff
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Breast Cancer Research 2011, 13:R121 doi:10.1186/bcr3067
Published: 28 November 2011
Abstract (provisional)
Introduction
The HER2-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate resistance mechanisms to each drug alone, or to their combination using a large panel of HER2-positive cell lines made resistant to these drugs.

Methods
Response to L+T treatment was characterized in a panel of 13 HER2-positive cell lines to identify lines that were de novo resistant. Acquired resistant lines were then established by long-term exposure to increasing drug concentrations. Levels and activity of HER2 and ER pathways were determined by qRT-PCR, immunohistochemistry, and immunoblotting assays. Cell growth, proliferation, and apoptosis in parental cells and resistant derivatives were assessed in response to inhibition of HER or ER pathways, either pharmacologically (L, T, L+T, or fulvestrant) or by using siRNAs. Efficacy of combined endocrine and anti-HER2 therapies was studied in vivo using UACC-812 xenografts.

Results
ER or its downstream products increased in 4 out of the 5 ER+/HER2+ lines, and was evident in one of the two intrinsically resistant lines. In UACC-812 and BT474 parental and resistant derivatives, HER2 inhibition by T reactivated HER network activity to promote resistance. T-resistant lines remained sensitive to HER2 inhibition by either L or HER2 siRNA. With more complete HER2 blockade, resistance to L-containing regimens required the activation of a redundant survival pathway, ER, which was upregulated and promoted survival via various Bcl2 family members. These L- and L+T-resistant lines were responsive to fulvestrant and to ER siRNA. However, after prolonged treatment with L, but not L+T, BT474 cells switched from depending on ER as a survival pathway, to relying again on the HER network (increased HER2, HER3 and receptor ligands) to overcome L's effects. The combination of endocrine and L+T HER2-targeted therapies achieved complete tumor regression and prevented development of resistance in UACC-812 xenografts.

Conclusions
Combined L+T treatment provides a more complete and stable inhibition of the HER network. With sustained HER2 inhibition, ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells. Complete blockade of the HER network, together with ER inhibition, may provide optimal therapy in selected patients.

[Firework]

Hmmmmmm.......I'll need to re-read when I'm feeling more capable of retaining this information.
Thank you for posting. I thought what had been said was chemo was less effective on HER 2...........
I'm not following the proper method of inquiry. When I see something in a "thread" and it peeks my interest or is something I've been trying to learn more about I asked about it.
Obviously, that's not what I should do.
Again, thank you for reposting these links for me to read.
Lorraine

[KakaCathFreeSpirit]

Thank-You Lani and Jackie07, I was riveted and feel optimistic about the latest research findings as well as your own research into the research, Thankyou from my heart, sincere regards catherine