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Promiscuous Her3 signaling; A New Target in the Treatment of Breast Cancer
Overactivity of Human Epidermal Growth Factor Receptor (HER) family tyrosine kinase (TK) signaling is a hallmark of breast cancers. This has led to the development of highly specific inhibitors of the HER family and all experimental evidence supports this treatment hypothesis. However HER family TK inhibitors appear to have limited clinical activities. The reasons for this are unclear and warrant further studies of HER family signaling. It is through heterodimerization and transphosphorylation that the HER family performs its signaling functions. Importantly, the regulation of downstream PI3K/Akt survival signaling is predominantly mediated through the transphosphorylation of the kinase-inactive Her3. Inhibition of HER family kinase activities should, in theory, lead to dephosphorylation of Her3 and suppression of all HER family signaling functions including PI3K/Akt pathway signaling. We have discovered a previously unknown potential for kinase infidelity inherent in Her3, which enables Her3 rephosphorylation despite suppression of HER family kinase activities, through yet undiscovered tyrosine kinases. The promiscuous nature of Her3 phosphorylation enables pathway switching in response to TK inhibitors and the ability for tumor cells to escape prolonged inactivation of the PI3K/Akt survival signaling pathway by these drugs. We propose to discover the molecular basis for promiscuous Her3 signaling. In our first specific aim we propose to identify the TK that mediates the rephosphorylation of Her3. This kinase will be identified from the entire human tyrosine kinome using microarray expression profiling, RT-PCR, tyrosine kinome siRNA library screening, and Akt substrate motif antibody techniques. In our second specific aim we will determine whether inhibition of downstream Her3 signaling, using an inhibitor of Akt, can significantly enhance the in vivo anti-tumor activity of a HER family TK inhibitor. All experimental evidence suggests that Her2 amplified tumors are driven by Her2, yet inhibition of Her2 kinase fails to deliver the promise of this oncogene hypothesis. We believe Her3 infidelity complicates this treatment hypothesis and needs to be considered. The characterization of this promiscuous signaling activity would be a breakthrough in our understanding of HER family signaling and will overcome a major obstacle in our efforts to effectively suppress this oncogenic signaling pathway.
Overactive HER family signaling is a hallmark of many breast cancers. Since these proteins signal predominantly by tyrosine phosphorylating eachother, much promise lies in the development of HER family specific tyrosine kinase (TK) inhibitors. However these agents appear to have little clinical activity. The reasons for this are not clear. We have discovered a previously unknown potential for kinase infidelity in the Her3 protein, which means that when the kinase function of the HER family is inhibited by the new TK inhibitors, Her3 goes outside the HER family and by way of another, yet unknown kinase, gets phosphorylated and maintains its signaling function. This escape route allows tumor cells to evade the lethal effects of the novel TK inhibitors. In order to develop highly effective therapies for HER family driven breast cancers, we must suppress Her3 effectively, including its previously unrecognized promiscuous signaling activities. Our first specific aim is to identify what other kinases phosphorylate Her3. We plan to search all the tyrosine kinases in the human genome using powerful techniques including microarray expression profiling, RT-PCR, and siRNA techniques. If we are able to identify the kinase responsible for Her3 phosphorylation, we can develop and use inhibitors of such a kinase in combination with HER family TK inhibitors to shut off Her3 signaling completely and kill tumor cells much more effectively. Our second specific aim is determine whether an existing inhibitor of downstream Her3 signaling can reverse resistance to HER family TK inhibitors.
Inhibition of an activated oncogene should, in principle, be a successful therapeutic approach in the treatment of oncogene-driven types of cancer. This approach has been validated in the development of Gleevec for the treatment of chronic myelogenous leukemia, where nearly 100% of the patients achieve complete remission with this drug. We think the same could be true for patients with HER family driven breast cancer, but the HER family is a complicated family and we believe we have discovered that it will require more than one drug to completely suppress its complex signaling functions. Successful accomplishment of our goals in this proposal would be a breakthrough in our understanding of HER family signaling and TK drug resistance and could lead to treatment strategies with much higher anti-tumor efficacy.