Overcoming resistance to HER2 inhibitors through state-specific kinase binding
Abstract
The heterodimeric receptor tyrosine kinase complex formed by HER2 and HER3 can act as an oncogenic driver and is also responsible for rescuing a large number of cancers from a diverse set of targeted therapies. Inhibitors of these proteins, particularly HER2, have dramatically improved patient outcomes in the clinic, but recent studies have demonstrated that stimulating the heterodimeric complex, either via growth factors or by increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes the activity of the inhibitors. To identify an inhibitor of the active HER2–HER3 oncogenic complex, we developed a panel of Ba/F3 cell lines suitable for ultra-high-throughput screening. We report medicinal chemistry on the hit scaffold resulted in a previously uncharacterized inhibitor that acts through preferential inhibition of the active state of HER2 and, as a result, is able to overcome cellular mechanisms of resistance such as growth factors or mutations that stabilize the active form of HER2.
- Authors:
-
- Univ. of California, San Francisco, CA (United States)
- California Inst. for Biomedical Research (Calibr), La Jolla, CA (United States)
- Univ. of Pennsylvania Perelman School of Medicine, Philadelphia, PA (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- Samuel Waxman Cancer Research Foundation; National Institutes of Health (NIH); American Heart Association (AHA); National Institute of General Medical Sciences (NIGMS)
- OSTI Identifier:
- 1357652
- Grant/Contract Number:
- R01 GM109176-01A1; 11PRE7670020; R01-GM099891
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Chemical Biology
- Additional Journal Information:
- Journal Volume: 12; Journal Issue: 11; Journal ID: ISSN 1552-4450
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Cancer therapy; High-throughput screening; Kinases; Small molecules
Citation Formats
Novotny, Chris J., Pollari, Sirkku, Park, Jin H., Lemmon, Mark A., Shen, Weijun, and Shokat, Kevan M. Overcoming resistance to HER2 inhibitors through state-specific kinase binding. United States: N. p., 2016.
Web. doi:10.1038/nchembio.2171.
Novotny, Chris J., Pollari, Sirkku, Park, Jin H., Lemmon, Mark A., Shen, Weijun, & Shokat, Kevan M. Overcoming resistance to HER2 inhibitors through state-specific kinase binding. United States. https://doi.org/10.1038/nchembio.2171
Novotny, Chris J., Pollari, Sirkku, Park, Jin H., Lemmon, Mark A., Shen, Weijun, and Shokat, Kevan M. Mon .
"Overcoming resistance to HER2 inhibitors through state-specific kinase binding". United States. https://doi.org/10.1038/nchembio.2171. https://www.osti.gov/servlets/purl/1357652.
@article{osti_1357652,
title = {Overcoming resistance to HER2 inhibitors through state-specific kinase binding},
author = {Novotny, Chris J. and Pollari, Sirkku and Park, Jin H. and Lemmon, Mark A. and Shen, Weijun and Shokat, Kevan M.},
abstractNote = {The heterodimeric receptor tyrosine kinase complex formed by HER2 and HER3 can act as an oncogenic driver and is also responsible for rescuing a large number of cancers from a diverse set of targeted therapies. Inhibitors of these proteins, particularly HER2, have dramatically improved patient outcomes in the clinic, but recent studies have demonstrated that stimulating the heterodimeric complex, either via growth factors or by increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes the activity of the inhibitors. To identify an inhibitor of the active HER2–HER3 oncogenic complex, we developed a panel of Ba/F3 cell lines suitable for ultra-high-throughput screening. We report medicinal chemistry on the hit scaffold resulted in a previously uncharacterized inhibitor that acts through preferential inhibition of the active state of HER2 and, as a result, is able to overcome cellular mechanisms of resistance such as growth factors or mutations that stabilize the active form of HER2.},
doi = {10.1038/nchembio.2171},
journal = {Nature Chemical Biology},
number = 11,
volume = 12,
place = {United States},
year = {Mon Sep 05 00:00:00 EDT 2016},
month = {Mon Sep 05 00:00:00 EDT 2016}
}
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