Novel Assay Is Focus of Drug Screening Research in Resistant Lung Cancer
Posted: Wednesday, March 25, 2020
For patients with treatment-resistant lung cancer, the live-cell mammalian membrane two-hybrid drug screening assay may provide physicians additional strategies to conventional drug-screening approaches in identifying receptor tyrosine kinases, according to research findings presented in Nature Chemical Biology. The live-cell platform for high-throughput identification of small molecules targeting functional protein-to-protein interactions of these kinases led Igor Stagljar, PhD, of the University of Toronto, and colleagues to identify four mutant-specific compounds, including two that would not have been identified by conventional in vitro kinase assays. Specifically, the FLT3 inhibitors gilteritinib and midostaurin—approved treatments of acute myeloid leukemia—will be studied further in patients with EGFR-mutant lung cancer.
“Drug resistance is a big problem for lung cancer patients,” said Dr. Stagljar, in a University of Toronto press release. “Our new technology allows us to find molecules that could be used against cancers for which no other treatment options are available.
In this study, the authors applied the novel assay to an oncogenic EGFR mutation that is resistant to the latest generation of clinically approved tyrosine kinase inhibitors. A screen of almost 3,000 molecules resulted in 4 “promising” compounds, with each one demonstrating no effect on the normal receptor. In addition to gilteritinib and midostaurin, another featured molecule was EMI1. This molecule acts on the mutant EGFR by targeting the receptor for degradation with the help of other molecular machineries, instead of inhibiting kinase activity. This type of mechanism of action may make it more difficult for tumors to develop resistance to the molecule, the authors proposed.
Disclosure: For full disclosure of the study authors, visit nature.com.