Overcoming resistance to HER2 inhibitors through state-specific kinase binding.
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. 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.
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.|Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.
Chris J
CJ
Novotny
California Institute for Biomedical Research (Calibr), La Jolla, California, USA.
Sirkku
S
Pollari
Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.|Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Jin H
JH
Park
Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.|Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Mark A
MA
Lemmon
California Institute for Biomedical Research (Calibr), La Jolla, California, USA.
Weijun
W
Shen
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.|Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.
Kevan M
KM
Shokat
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D055550:Protein Stability / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse