Understanding HER3 and mTor Signaling in Breast Cancer

Institution: University of California, San Francisco
Investigator(s): Mark Moasser, M.D. -
Award Cycle: 2012 (Cycle 18) Grant #: 18IB-0030 Award: $100,000
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2012)

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.

Final Report (2014)

A principal barrier to the highly effective treatment of HER2-amplified breast cancers is the robust tumor addiction to HER2. This addiction underlies powerful and resourceful mechanisms that enable tumors to evade the lethal effects of HER2-targeted therapies. These effects are in large part, mediated through HER3. HER3 is linked with the downstream mTor signaling network, which is a highly conserved signaling network reconciling many cellular functions with environmental inputs, and is by nature highly adaptational. Although HER3 normally functions as an upstream growth factor signaling input, we find that in HER2-amplified tumor cells it functions as an essential node in the adaptational network. In this project, we sought to understand what makes HER3 a requisite node in this tumor type.

A chemical-biologic approach was used in conjunction with genetic-biologic approaches to query response to perturbation in the entire signaling network downstream of HER3/PI3K. This was initially done in HER2-amplified SkBr3 cells and subsequently in untransformed MCF10A cells. The signaling network in these two cell types were compared, and the key findings then confirmed in a much larger panel of tumor cells and mammary epithelial cells. A key attribute of HER2-amplified tumors is that mTORC2 is driven by Akt, creating a feed-forward Akt-mTORC2 interdependency that coopts HER3 as a buffering node, integrally involved in the active signaling throughput underlying preservation of cellular homeostasis. A critical pathophysiological event in the evolution of HER2-driven breast cancers is the loss of the input signals that normally maintain constitutive mTORC2 signaling, repositioning it under Akt dependency. Better definition of the signals through which Akt drives mTORC2 will offer a new paradigm for the development of treatments that are very likely to be highly synergistic with HER2-targeting therapies.

•Effective treatment of HER2-amplified breast cancer by targeting HER3 and beta integrin

Effective treatment of HER2-amplified breast cancer by targeting HER3 and ß1 integrin doi:10.1007/s10549-016-3698-y
Periodical:Breast Cancer Research and Treatment
Index Medicus: Breast Cancer Res Treat
Authors: M R. Campbell, H Zhang, S Ziaee, A. Ruiz-Saenz, N Gulizia, J Oeffinger, D N Amin, et al.
Yr: 2016 Vol: 155 Nbr: 3 Abs: Pg:431-40