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  2. EGFR signaling and pharmacology in oncology revealed with innovative BRET-based biosensors

EGFR signaling and pharmacology in oncology revealed with innovative BRET-based biosensors

  • Commun Biol. 2024 Mar 1;7(1):250. doi: 10.1038/s42003-024-05965-5.
Florence Gross 1 Arturo Mancini 1 Billy Breton 2 Hiroyuki Kobayashi 2 Pedro Henrique Scarpelli Pereira 2 Christian Le Gouill 2 Michel Bouvier 2 Stephan Schann 3 Xavier Leroy 3 Laurent Sabbagh 4
Affiliations

Affiliations

  • 1 Domain Therapeutics North America Inc., 7171 Frederick-Banting, Saint-Laurent, Quebec, H4S 1Z9, Canada.
  • 2 Institute for Research in Immunology and Cancer, and Department of Biochemistry and Molecular Medicine, University of Montreal, 2950 Chemin de Polytechnique, Montreal, Quebec, H3T 1J4, Canada.
  • 3 Domain Therapeutics SA, 220 Boulevard Gonthier D'Andernach, 67400, Strasbourg-Illkirch, France.
  • 4 Domain Therapeutics North America Inc., 7171 Frederick-Banting, Saint-Laurent, Quebec, H4S 1Z9, Canada. lsabbagh@domaintherapeutics.com.
Abstract

Mutations of Receptor Tyrosine Kinases (RTKs) are associated with the development of many cancers by modifying receptor signaling and contributing to drug resistance in clinical settings. We present enhanced bystander bioluminescence resonance energy transfer-based biosensors providing new insights into RTK biology and pharmacology critical for the development of more effective RTK-targeting drugs. Distinct SH2-specific effector biosensors allow for real-time and spatiotemporal monitoring of signal transduction pathways engaged upon RTK activation. Using EGFR as a model, we demonstrate the capacity of these biosensors to differentiate unique signaling signatures, with EGF and Epiregulin ligands displaying differences in efficacy, potency, and responses within different cellular compartments. We further demonstrate that EGFR single point mutations found in Glioblastoma or non-small cell lung Cancer, impact the constitutive activity of EGFR and response to tyrosine kinase inhibitor. The BRET-based biosensors are compatible with microscopy, and more importantly characterize the next generation of therapeutics directed against RTKs.

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