Understanding HER3 and mTor Signaling in Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: While the abnormal functions of HER2 underlie the pathogenesis of some breast cancers, the tumor cell “addiction” to continued HER2 signaling provides an opportunity for intervention and has formed the basis for the development of a generation of anti-cancer drugs, such as Herceptin. However, in actual clinical practice patients inevitably develop resistance through mechanisms that restore the functions of HER2 and its signaling partner HER3. As such, the addiction to HER2-HER3 signaling is the principal force driving this disease to its lethal endpoint. Understanding the mechnisms underlying this addiction is of paramount importance. Our hypothesis is that the association of HER3 into the mTor signaling network mediates a fundamental shift in cellular programming. The mTOR protein complex in cells integrates the input from upstream pathways to regulate nutrient/energy levels and protein synthesis. mTOR inhibitors (e.g., rapamycin) are already in clinical use to prevent transplant rejection, and new mTor inhibits are being investigated for a variety of cancers and other diseases. 
 
 
 
 
 
 
 
 We will use a small molecule library approach to map the “adaptational network topology” (i.e., signaling pathways) downstream of HER3 in MCF10A cells. This involves a pharmacologic library of up to 15 compounds inhibiting various nodes in the HER3 signaling network. This chemical-genetic analysis combined with selective molecular-genetic interventions will expand our understanding of HER3-Akt-mTor signaling in breast cancer cell lines, such as SkBr3. In parallel, we will conduct a similar analysis of HER3-Akt-mTor signaling in untransformed MCF10A breast epithelial cells. Ultimately, we will undertake a comparison of the transformed (SkBr3) and untransformed (MCF10A) states in cell signaling and identify the key differences that define the state of HER3 addiction. This work will be done in collaboration with a computational biologist and pioneer in the analysis of adaptational signaling topologies. The result of these studies will provide important clues as to potential new target to break the connection between HER3 and mTor as a new approach for further investigation in the clinical setting. 
 
 
 
 
 
 
 
 Our ultimate goal is to develop an entirely new paradigm for the treatment of breast cancer. We believe the relentless and addictive behavior of HER2-driven breast is caused not just by virtue of the genetic changes, but rather are powered by aberrant constitutive cellular circuitries that were developed over a billion years of evolution. Since the coupling of HER2 and HER3 to the endogenous cell circuitry underlies the pathogenesis of this disease, we should be able to develop treatments to uncouple them. Such treatments target the true driver of the disease and are likely to alter the natural course of this disease in a much more substantial way than current attempts to directly target and inhibit HER2 or HER3, which tumors can readily overcome in many patients.