Exploring a new mechanism of drug resistance using next-generation computer modeling
Small molecule therapeutics is a type of cancer treatment that precisely targets proteins that control how cancer cells grow and spread. This treatment is expected to turn off the signals that tell cancer cells to grow, and eventually kill them. However, cancer cells are evolutionary smart, adapt to targeted therapies and continue to grow.
Current clinically used RAF inhibitors efficiently block oncogenic MAPK signals in RAF-mutant cancers, yet they paradoxically amplify ERK activity instead of inhibiting it in RAS-mutant cancer cells. An archetypal question in this context is why RAF inhibitors do not work. Several mechanisms are known to adapt to small molecule inhibitors, resulting in drug resistance. In this paper, we explored mechanisms of drug resistance where the cell’s exposure to RAF inhibitor results in the increase in the abundance of the different RAF protein isoforms.
We used a combined experimental and computational approach to find ways that overcome the resistance. A key challenge in modeling biochemical systems is to properly describe complex protein-drug interactions. With classic kinetic modeling, it is difficult to incorporate allosteric effects caused by kinase inhibitors as they alter the binding affinities depending on the protein status. Therefore, we used structure-based modeling that not only integrates protein-protein interactions, but also includes thermodynamics, protein-drug interactions, and structural elements of the target protein. Our next-generation computer models and in vitro experiments demonstrate that a combination of conformation‑selective RAF inhibitors is effective for overcoming the resistance brought about by RAF overexpression. Because the model assumptions are based on fundamental thermodynamic principles, we anticipate the therapeutic strategy derived from the model is applicable to any kinases that undergo dimerization during physiological activation and facilitated by kinase inhibitors.
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See the full Open Access research article, "A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression," published in Biomolecules here.
This blog first published as news article on the UCD School of Medicine website, 9 August 2023.
