 |
The study, led by the Science and Technology Facilities Council (STFC) Central Laser Facility (CLF) with support from the Imaging Therapies and Cancer Group at King's, used advanced laser imaging techniques to identify structural details of a mutated protein which help it to evade drugs that target it.
The study was published in the journal Nature Communications and lays the groundwork for future research into more effective, long-lasting cancer therapies.
The Epidermal Growth Factor Receptor (EGFR) is a protein that sits on the surface of cells and receives molecular signals that tell the cell to grow and divide. In certain types of cancer, mutated EGFR stimulate uncontrolled growth, resulting in tumors.
Various cancer treatments block and inhibit mutant EGFR to prevent tumor formation, but these are limited as eventually cancerous cells commonly develop further EGFR mutations that are resistant to treatment.
Until now, how exactly these drug-resistant EGFR mutations drive tumor growth was not understood, hindering our ability to develop treatments that target them.
In this latest study, scientists at CLF have obtained super-resolution images of a drug-resistant EGFR mutation known to contribute to lung cancer. This was achieved using an advanced laser imaging technique developed by STFC for this purpose called Fluorophore Localization Imaging with Photobleaching, or FLImP.
FLImP analysis revealed structural details as small as two nanometers and showed for the first time with this level of precision how molecules in the drug-resistant EGFR mutation interact.
Additional analysis by the Biomolecular & Pharmaceutical Modeling Group at University of Geneva (UNIGE) used advanced computer simulations that combined with the FLImP analysis were able to provide atomistic details of the mutant EGFR complexes.
From this, the team were able to compare the structural details of the mutated and healthy EGFR to identify interfaces between interacting molecules in the drug-resistant mutation critical for tumor growth.
The team then introduced additional mutations to the drug-resistant EGFR in in cultured lung cells and in mice that interfered with the newly discovered interfaces.
In these experiments, one of the additional EGFR mutations was shown to block cancer growth, with mice developing no tumors, further indicating that the ability of this EGFR mutation to promote cancer indeed depends on these interfaces.
Published in journal: Nature Communications
Title: Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers
Authors: R. Sumanth Iyer, Sarah R. Needham, Ioannis Galdadas, Benjamin M. Davis, Selene K. Roberts, Rico C. H. Man, Laura C. Zanetti-Domingues, David T. Clarke, Gilbert O. Fruhwirth, Peter J. Parker, Daniel J. Rolfe, Francesco L. Gervasio, and Marisa L. Martin-Fernandez
Source/Credit: King's College London
Reference Number: bmol033124_01