The endeavor to treat HER2-amplified cancers through the inactivation of HER2 has proven more difficult than anticipated. The clinical activities of HER2 kinase inhibitors are weak, and better results with HER2 antibodies occur without the disruption of signaling, likely through immunologic mechanisms. The endeavor to inactivate the oncogenic function of HER2 awaits deeper mechanistic insights. Our work has highlighted the critical role of its partner HER3. Although kinase-inactive, HER3 is a functionally active and requisite partner of HER2 in this disease, and its dynamic regulation by a complex downstream network topology can upregulate HER2-HER3 signaling output 100-fold, undermining the efficacies of all forms of HER2 or HER3-targeted therapies. Effective suppression of the functionally relevant HER2-HER3 tumor driver requires deeper insights into the mechanism of signal generation in the pathologic state of HER2 overexpression. We have conducted a structure-function biochemical analysis of HER2-HER3 transactivation, specifically in the state of HER2 overexpression, revealing deeper insights into the mechanism of signal generation in this disease state. We find that the constitutive phosphorylation of HER3 occurs through interactions that do not require extracellular domain (ECD) activation or dimerization, or even proximity, defying the well described mechanisms for normal physiological signaling in this receptor family. However, HER2-HER3 activation does require kinase domain (KD) interactions, which in lieu of ECD-driven proximation events, are stoichiometrically driven by massive HER2 expression seen in these tumors. The evidence reveals functions in the HER3 KD including a function in its c-lobe as an allosteric activator of HER2 KD, a function in its n-lobe surface pocket, a function in the HER2 KD allosteric receiver site, and an unexpected requirement for the HER2 c-tail in promoting HER3 signaling. These data suggest that the plethoras of ECD-targeting approaches being pursued in the biotech sector are unlikely to yield highly effective therapies for HER2-amplified cancers. Rather it redirects this endeavor towards a focus on targeting kinase domain functions. In the next few years of this project we propose to establish the relevance of these findings to the in vivo tumorigenic growth of HER2- amplified breast cancers. In the first aim we will determine whether the described ligand and ECD-independent constitutive HER2-HER3 signal is the actual driver of tumorigenic growth in vivo. The impact of proximity restricting therapeutic modalities will also be tested. In the second aim we will test several newly discovered strategies targeting the KDs of HER2 and HER3 in the treatment of HER2-amplified cancers in vivo. In the third aim we will explore the more vaguely defined role of the HER2 and HER3 c-tails as either simple signaling substrates or functionally more involved in oligomerization and signal generation. These studies will define the rate-limiting steps for signal generation and tumorigenic growth in cancer cells driven by HER2 overexpression, laying the foundation for the development of highly effective therapies for HER2-amplified cancers.

Public Health Relevance

Unlike other tyrosine kinase oncogenes, attempts to treat HER2-driven cancers through HER2-targeting therapies have produced only modestly active drugs. Our work has revealed that this is due to the failure to inactivate the resilient HER2-HER3 driver of this disease. In this project we are proposing to better understand how the tumorigenic signal is generated by this tumor driver, laying the groundwork for the development of highly effective targeted therapies for HER2-amplified cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA122216-06A1
Application #
8578421
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2006-07-01
Project End
2018-05-31
Budget Start
2013-07-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$295,885
Indirect Cost
$107,523
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Campbell, Marcia R; Zhang, Hui; Ziaee, Shabnam et al. (2016) Effective treatment of HER2-amplified breast cancer by targeting HER3 and β1 integrin. Breast Cancer Res Treat 155:431-40
Campbell, Marcia R; Moasser, Mark M (2015) HER Targeting in HER2-Negative Breast Cancers: Looking for the HER3 Positive. Clin Cancer Res 21:2886-8
Amin, Dhara N; Ahuja, Deepika; Yaswen, Paul et al. (2015) A TORC2-Akt Feed-Forward Topology Underlies HER3 Resiliency in HER2-Amplified Cancers. Mol Cancer Ther 14:2805-17
Ruiz-Saenz, A; Sandhu, M; Carrasco, Y et al. (2015) Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum. Oncogene 34:5288-94
Moasser, Mark M; Krop, Ian E (2015) The Evolving Landscape of HER2 Targeting in Breast Cancer. JAMA Oncol 1:1154-61
Amin, Dhara N; Ruiz-Saenz, Ana; Gulizia, Nathaniel et al. (2015) Chemical probing of HER2-amplified cancer cells identifies TORC2 as a particularly effective secondary target for combination with lapatinib. Oncotarget 6:41123-33
Moasser, Mark M (2014) Two dimensions in targeting HER2. J Clin Oncol 32:2074-7
Littlefield, Peter; Moasser, Mark M; Jura, Natalia (2014) An ATP-competitive inhibitor modulates the allosteric function of the HER3 pseudokinase. Chem Biol 21:453-8
Amin, Dhara N; Sergina, Natalia; Lim, Lionel et al. (2012) HER3 signalling is regulated through a multitude of redundant mechanisms in HER2-driven tumour cells. Biochem J 447:417-25
Campbell, Marcia R; Amin, Dhara; Moasser, Mark M (2010) HER3 comes of age: new insights into its functions and role in signaling, tumor biology, and cancer therapy. Clin Cancer Res 16:1373-83

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