An Entirely New Approach Makes Tumor Cells Easier To Destroy
In a groundbreaking discovery, scientists have unveiled that a crucial interface within a protein implicated in cancer progression could serve as a promising target for enhanced treatment strategies.
Conducted by the Science and Technology Facilities Council (STFC) Central Laser Facility (CLF), the study utilized cutting-edge laser imaging techniques to dissect the structural intricacies of a mutated protein. These insights illuminate how the protein evades drugs designed to inhibit it, marking a significant advancement in understanding cancer biology.
It was published in the journal Nature Communications, and it establishes the framework for the next investigations into more potent, long-lasting cancer treatments.
A protein called the epidermal growth factor receptor (EGFR) is present on the surface of cells and is responsible for detecting chemical cues that instruct cells to proliferate and divide. A mutation in EGFR causes uncontrolled growth in certain cancer types.
Various cancer therapies block and inhibit mutant EGFR to prevent tumor growth, but their effectiveness is limited because malignant cells frequently produce further EGFR mutations that are resistant to therapy.
Until recently, it remained unclear how these drug-resistant EGFR mutations cause tumor development, limiting our ability to create drugs that target them.
In their most recent investigation, researchers at CLF have successfully captured super-resolution images of a drug-resistant mutation of the Epidermal Growth Factor Receptor (EGFR), a notorious contributor to lung cancer. Employing a sophisticated laser imaging technique pioneered by STFC specifically for this purpose, known as Fluorophore Localisation Imaging with Photobleaching (FLImP), scientists achieved unprecedented clarity in visualizing the intricate structure of the mutated EGFR.
Through FLImP analysis, scientists were able to discern structural nuances as minute as two nanometres, offering an unprecedented glimpse into the molecular interactions of the drug-resistant EGFR mutation. This marks the first instance where such precision has been attained, significantly advancing our understanding of how molecules within the mutated EGFR variant behave.
Furthermore, researchers from the Biomolecular & Pharmaceutical Modelling Group at the University of Geneva (UNIGE) conducted sophisticated computer simulations, complementing the FLImP analysis. Together, these analyses provided atomistic insights into the complex architecture of the mutant EGFR, shedding light on its behavior at the molecular level.
This allowed the team of investigators to examine the structural characteristics of the healthy and mutant forms of EGFR and determine which molecular interfaces in the drug-resistant mutation were important for the formation of the tumor.
The study’s leader, Professor Marisa Martin-Fernandez of CLF, noted, “we’re extremely excited about its potential to inform the course of cancer research going forward. If this interface proves to be an effective therapeutic target, it could provide an entirely new approach to much needed pharmaceutical development.”
Dr. Yiannis Galdadas at UNIGE, who performed the simulations, added: “The simulations were able to push the effective resolution of the microscope beyond the limits of imagination. It’s almost possible to ‘touch’ the mutation site and see its effect.”
Subsequently, the research team introduced further mutations to the drug-resistant EGFR in cultured lung cells and in mice, targeting the newly identified interfaces.
Through these experiments, one of the additional EGFR mutations effectively halted cancer growth, leading to the absence of tumors in mice. This compelling outcome underscores the critical role of these interfaces in driving cancer progression via EGFR mutations.
Encouragingly, scientists envision these interfaces as promising targets for novel cancer therapies aimed at circumventing resistance associated with EGFR mutations.
The study methodology is presently being tested on other EGFR mutations known to be associated with lung cancer at CLF. Additionally, they want to determine whether this interaction contributes to the growth of malignancies other than brain cancer.