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Gregory J. Riely, MD, PhD
Gregory J. Riely, MD, PhD
Posted: Wednesday, April 17, 2024
Mutations in EGFR are often a hallmark of lung cancer; however, understanding how these mutations perpetuate drug resistance is not well understood. An article published in Nature Communications presented findings from a preclinical study that assessed whether the drug-resistant EGFR mutations drive tumor growth and highlighted the possible molecular mechanisms involved. Francesco Luigi Gervasio, PhD, of University College, London, and the University of Geneva, and colleagues used fluorophore localization imaging with photobleaching (FLImP) combined with advanced computer simulations to assess EGFR structure on the atomic level. Their findings highlighted specific structure and assembly mechanisms of ligand-free, kinase-active oligomers with oncogenic functions that may drive tumor growth.
“If this interface proves to be an effective therapeutic target, it could provide an entirely new approach to much-needed pharmaceutical development,” stated study coauthor Professor Marisa Martin-Fernandez, of Central Laser Facility, UKRI-STFC Rutherford Appleton Laboratory, Didcot, United Kingdom, in a press release.
Chinese hamster cells expressing specific EGFR mutations were generated and used for various in vitro and imaging analyses. Specifically, a high-resolution FLImP was used in conjunction with molecular dynamics simulations to measure specifically labeled dimers and oligomers on cells. A total of 24 young adult male mice were used for in vivo tumor imaging. Confocal imaging was also used to conduct anti-EGFR affibody and EGFR competition-binding experiments to identify specific binding affinity.
Analysis of the cells expressing specific wild-type EGFR and EGFR mutations showed that approximately 20% to 30% of EGFRs were incorporated in dimers and between 15% and 40%, in oligomers. After treatment with a conformation-reflective monoclonal antibody, mAb-2E9, the conformation of the three ligand-free dimer subunits was found. To assess the relevance of the proposed ligand-free oligomer structure and assembling mechanisms in vivo, the interleukin 3–dependent murine lymphoid Ba/F3 cell system was employed. The growth pattern observed showed that Ba/F3 + T766M tumors grew best, followed by the double-mutant tumors, whereas wild-type EGFR tumors did not grow.
Disclosure: The study authors reported no conflicts of interest.
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