| Authors |
Punit Saraon, Jamie Snider, Yannis Kalaidzidis, Leanne E Wybenga-Groot, Konstantin Weiss, Ankit Rai, Nikolina Radulovich, Luka Drecun, Nika Vučković, Adriana Vučetić, Victoria Wong, Brigitte Thériault, Nhu-An Pham, Jin H Park, Alessandro Datti, Jenny Wang, Shivanthy Pathmanathan, Farzaneh Aboualizadeh, Anna Lyakisheva, Zhong Yao, Yuhui Wang, Babu Joseph, Ahmed Aman, Michael F Moran, Michael Prakesch, Gennady Poda, Richard Marcellus, David Uehling, Miroslav Samaržija, Marko Jakopović, Ming-Sound Tsao, Frances A Shepherd, Adrian Sacher, Natasha Leighl, Anna Akhmanova, Rima Al-Awar, Marino Zerial, Igor Stagljar
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| Abstract |
Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches. |