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Although the amplification and overexpression of HER2 is the oncogenic event underlying this type of cancer, it is now clear that HER3 plays a critical role in the progression of these cancers and the inactivation of constitutive HER2-HER3 signaling has turned out to be much more difficult than had been anticipated. Our efforts in this arena are currently focused on several aspects of HER2-HER3 driven tumorigenic signaling. Some are described below.


schematic of interests


HER2-HER3 Signal generation

Work of the past decade has provided significant insight into the structural basis for the ligand-induced activation, dimerization, and transphosphorylation of HER family receptors. But many of the restraints built into the physiological mode of signaling are disrupted and overcome in the pathologic state of HER2 overexpression. Through structure-function studies spanning the realms of biochemistry to cell-based and in vivo models, we seek to understand how the massive overexpression of HER2 generates constitutive HER2-HER3 signaling, and how this differs from the normal physiological mode of regulated HER2-HER3 signaling.


Understanding the HER3-linked downstream network topology

The anti-tumor activities of all classes of HER2-targeting drugs are undermined by a robust signal-buffering capacity inherent in the HER2-HER3 tumor driver and an ability to substantially and rapidly increase its signaling output to compensate for the suppressive effects of inhibitory drugs. This compensatory effect is driven by a highly competent downstream network topology linked with HER3 signaling, involving the evolutionarily conserved mTor signaling network. Using genetic and chemical genetic approaches combined with tools of computational biology, we seek to obtain a deeper understanding of this downstream network topology. In particular we are interested in how the network is altered in HER2-amplified tumor cells, and why HER3 has become an essential node in this fundamentally important eukaryotic mechanism for cellular homeostasis.


Understanding HER2 addiction

The experience with the first generation of kinase inhibitors targeting kinase oncogenes has confirmed the important role of many of these oncogenes in human cancers, but has also revealed highly resourceful cellular mechanisms that can overcome the inhibitory effects of inhibitors, either through restoration of kinase signaling, or reprogramming of cellular circuitries to bypass the targeted kinase oncogene. It is now apparent that the cellular addiction to the kinase oncogene may be the true driver of disease progression, not the oncogene itself. This is nowhere more apparent than in the case of HER2-driven cancers, where HER2-HER3 signaling output is restored within hours of initial inhibition by drugs, creating upfront resistant to most agents targeting HER2 or HER3. We are interested in understanding the molecular basis for tumor cell addiction to HER2. This includes specific interrogation of the pathways that link HER2-HER3 signaling to the regulation of cell metabolism, or apoptotic programs, and unbiased whole genomic approaches to identify genes mediating addiction to HER2.