Combination Overcomes Breast Cancer Resistance to Herceptin
UT MD Anderson scientists find adding SRC inhibitor breaks hub of opposition
HOUSTON — Breast cancer tumors take numerous paths to
resist the targeted drug Herceptin, but a single roadblock at a
crucial crossroads may restore a tumor's vulnerability to
treatment, scientists at The University of Texas MD Anderson Cancer
Center report on line at Nature Medicine.
Adding the drug saracatinib to Herceptin treatment shrinks
previously resistant tumors by cutting off at least five different
molecular pathways, each of which can resist, said senior author
Dihua Yu, M.D., Ph.D., professor in MD Anderson's Department of
Molecular and Cellular Oncology.
"Scientists have identified so many ways by which a tumor resists
Herceptin that it raises an important issue for treatment," Yu
said. "Will we have to give patients six drugs or 10 drugs to block
them all? The side effects would be awful. Two pills are better.
This combination is a promising therapy for those with
Herceptin-resistant breast cancer."
Working in cell lines, mouse models of breast cancer and checking
their work in human tumor samples, Yu and colleagues identified
SRC, a known cancer-promoting protein, as the crucial common
downstream component of multiple resistance pathways.
Saracatinib is an SRC inhibitor, thwarting that protein and
allowing Herceptin to work again in tumors that have a high amount
of the HER2 protein.
Only about 26 percent of women with HER2-positive breast cancer
respond to Herceptin as single therapy. Between 40 and 60 percent
respond to the drug when combined with other chemotherapy.
Combination is ready for clinical trials
Yu said saracatinib has been tested in phase I and phase II
clinical trials as a single treatment against late-stage cancers.
It has a favorable side effects profile.
"It didn't work as a single agent, but very few drugs work by
themselves against late stage disease," Yu said. "Our experiments
confirmed its lack of efficacy as a sole treatment. But combined
with Herceptin, it's beautiful."
Another SRC inhibitor, dasatinib, has been approved by the U.S.
Food and Drug Administration as an anti-cancer drug, but it has
harsher side effects, said Siyuan Zhang, Ph.D., a postdoctoral
fellow in Yu's lab and the paper's first author.
A tumor-suppressor's job
In 2004, Yu's lab discovered that loss of the tumor-suppressing
gene known as PTEN led to Herceptin-resistant tumors. PTEN is a
phosphotase - a protein whose function is to strip phosphate
chemical groups off of other molecules.
PTEN has two components, one to remove phosphate groups from
lipids, and another to remove them from proteins. PTEN's target
protein however, was unknown.
Zhang discovered that SRC is a PTEN target. With its phosphate
groups, SRC is active. PTEN stifles SRC by peeling away the
phosphates.
If PTEN loss leads to Herceptin resistance, and PTEN targets SRC,
would that make SRC the culprit?
On the trail of SRC
In a series of experiments the researchers found:
SRC is active in breast cancer cells once vulnerable but now
resistant to Herceptin and in cells that are resistant from the
start.
Activation of SRC drives resistance to Herceptin. Tumors with low
SRC levels treated by Herceptin shrunk to 20 percent of their
original volume in 21 days while SRC-heavy tumors increased by
nearly 400 percent over the same time in mouse experiments.
SRC activity correlates with patient response to Herceptin.
Assessing SRC activation in samples of 57 human breast cancer
tumors, the team found that more than 90 percent of tumors with low
SRC responded compared with 40 percent of tumors with active
SRC.
Patients with little active SRC had a median survival of 57.9
months compared with 34.2 months in those with high SRC
activity.
SRC is activated by a number of receptor tyrosine kinases that
cause resistance, including IGF-1R, EGFR, ERBB2, HER3, and Met,
separate pathways that work through SRC. "Block SRC, and you
reverse them all," Zhang said.
Crushing resistance
Combining Herceptin and saracatinib to treat resistant tumors in
mice reduced tumor volume by 90 percent in 25 days. Herceptin alone
kept tumor volume about the same during the same period, while
control and saracatinib alone permitted growth of more than 200
percent.
The difference was more striking in tumors deficient in SRC's
enemy, the PTEN tumor-suppressor. The combination reduced tumor
volume by more than 90 percent while the two drugs alone allowed
growth of between 200 and 400 percent.
This study was funded by grants from the National Cancer Institute,
MD Anderson Breast Specialized Program of Research Excellence;
Department of Defense Center of Excellence; Susan G. Komen Breast
Cancer Foundation Promise Grant; the Cancer Prevention and Research
Institute of Texas, the MD Anderson Breast SPORE Career Development
Award and Susan G. Komen Breast Cancer Foundation Postdoctoral
Fellowship.
Co-authors with Zhang and Yu are: Wen-Chien Huang, M.D., Ping Li,
Hua Guo, M.D., Say-Bee Poh, M.D., Samuel W. Brady, Yan Xiong, M.D.,
Ling-Ming Tseng, M.D., Shau-Hsuan Li, M.D., and Zhaoxi Ding M.D.,
all of MD Anderson's Department of Molecular and Cellular Biology;
Aysegul A. Sahin, M.D., MD Anderson Department of Pathology; and
Francisco J. Esteva, M.D., Ph.D., and Gabriel N. Hortobagyi, M.D.,
of MD Anderson's Department of Breast Medical Oncology. Brady is a
graduate student in The University of Texas Graduate School of
Biomedical Sciences at Houston, a joint operation of MD Anderson
and The University of Texas Health Science Center at Houston
(UTHealth).
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Posted: March 2011
