http://www.ucsfbreastcarecenter.org/aboutindex5.htmlT
HER2 and the Power of Translational Research: Part II
Continued from the BCC Newsletter, Spring, 2009
BREAST CARE CENTER NEWSLETTER • fall 2009 3
While it had been thought for many years that the activating partner for HER2 could be another HER2 protein, our laboratory research group and others discovered that this partner is actually its sister protein HER3. In fact HER2
cannot cause breast cancer without the help of HER3 and research in our laboratory has now re-defined the causative
driver of this disease as the HER2-HER3 dimer, not just HER2.
Too much HER2-HER3 interaction leads to uncontrolled and irrational cancer cell behavior and growth and dysfunction of the many cellular mechanisms that ordinarily makes cells respect their neighbors and not damage each other.
We have found that HER2-HER3 signaling in cancers is much more difficult to inactivate with the current types
of drugs than would have been predicted. This is because HER3 brings to the complex many mechanisms to
protect it, exemplifying how important the HER2-HER3 complex is in cancer cells.
Inactivating HER2-HER3 is possible, but it requires much higher doses of our current types of drugs, or a new generation of drugs that acts through new mechanisms. We are currently testing
the effect of much higher dosing of a HER2 inhibitor in a clinical trial at our center with the hope that high doses can cripple HER2-HER3 signaling.
Ultimately, our studies suggest that to treat this disease very effectively
we need to stop the HER2-HER3 complex
either by preventing them from coming together or preventing HER3 from activating HER2. Our laboratory is working on the details of how the HER2-HER3 handshake takes place, how the HER3 key fits into the HER2 ignition, and what kind of drug it takes to interfere with the HER2-HER3 interaction and to completely inactivate this complex.
We believe that the next generation of therapies that arise from this research will finally be the ones that will eradicate
this disease in affected patients. We are working towards this endeavor in collaboration with numerous other scientists, including scientists who create new types of drugs, scientists who study the structures of proteins, and scientists who study many of the other signaling proteins that are affected by HER2 and HER3.
Nature developed mechanisms whereby HER2 and HER3 are kept apart and only allowed to come together in certain panic situations when cells are under stress, or under inflammation, or need help to survive. However, this
restraint is overcome in HER2-positive breast cancer cells because the massive amount of HER2 essentially ambushes
HER3, overriding the natural restraints that limit their interactions and turning on cell signals that are highly inappropriate leading to malignant behavior.These revelations have now made transparent the inner workings of these cancer cells, identifying the key culprits and events, and efforts to intervene are underway. The dedication of researchers is absolute, and their will inexhaustible.
As long as people and government continue to fund these efforts, and patients continue to participate in studies, the future holds great promise that the curse of this disease will eventually be lifted.
Dr. Moasser is a Medical Oncologist in the
UCSF Breast Care Center and Associate
Professor in Residence, Department of
Medicine, Division of Hematology/Oncology.
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