Understanding why and how resistance to chemotherapy occurs is an important step toward optimizing cancer treatments. A team of scientists including Markus Seeliger, PhD, of the Renaissance School of Medicine at Stony Brook University, believes they have found a new process through which drug resistance occurs. They are using a computer simulation model that helps them understand exactly how molecules interact with the cancer drug Imatinib (known as Gleevec) in the chemotherapy-resistant process. Imatinib treats chronic myeloid leukemia (CML) very effectively, but many late-stage patients experience drug resistance that makes the drug minimally effective at this stage.
The research is highlighted in an article published in Angewandte Chemie, a major chemistry journal, and is based on previous detailed research in 2021 in PNAS.
Imatinib inhibits the protein kinase BCR-Abl, an overly active cellular signaling machinery in CML. In the PNAS study, researchers showed that variations in the kinase construction plan can make it difficult for Imatinib to bind to kinase and also accelerate the release of kinase drugs. In the paper Angewandte Chemie, the research team adopted the computational methodology, developed by co-author Pratyush Tiwary of the University of Maryland, which allowed them to study the very slow release of imatinib from kinase.
This method in itself is an important technical achievement that expands the computational capabilities for drug resistance research and, above all, led us to predict how quickly healthy and mutant proteins would release this drug. For the first time, we were able to see the release of a drug from a protein in such detail and precision. In addition, we could show that the mutation changes fundamentally within the protein drug’s exit pathway.
This is important because the rate of drug release can be as important to a drug’s therapeutic effect as the strength of a drug’s binding to the protein. “
Markus Seeliger, PhD, Associate Professor, Department of Pharmacological Sciences, Renaissance School of Medicine at Stony Brook University
Seeliger further explains that the method could provide a basis for understanding the molecular mechanisms behind resistance to chemotherapy.
More broadly, the implications of what they discovered are that if scientists can understand how drugs are released from their proteins, they may be able to design drugs with slower release and higher therapeutic impact. In addition, if the rapid release of the drug could cause drug resistance, and doctors can show that this is happening, they may be able to reactivate the effectiveness of the drug by asking the patient to take the drug more often.
The basis for mutation testing using the computational method was described in the PNAS document. Seeliger and colleagues tested how imatinib binds to mutations in patients with imatinib-resistant CML. They found that most mutations bind easily to imatinib, so you raised the question of how do these mutations cause resistance in patients? The researchers then identified several mutants that bind easily to imatinib, but release the drug much more quickly.
After identifying these mutants with faster drug release, the team used nuclear magnetic resonance (NMR) and molecular dynamics to link the protein to the dissociation of the drug, underlying the importance of the dissociation kinetics of the drug. drug for drug efficacy. This allowed them to identify a new mechanism of resistance to imatinib.
The work that resulted in the paper published in PNAS involved the collaborative efforts of Seeliger and colleagues at Stony Brook, and researchers at the Memorial Sloan Kettering Cancer Center and Goethe University in Frankfurt, Germany.
The research that led to the most recent article was led by Tiwary and colleagues at the University of Maryland, in collaboration with Seeliger and scientists from the Broad Institute at MIT and Harvard University.
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Magazine reference:
Shekhar, M., et al. (2022 Differentiation of protein dissociation pathway and flexibility may explain the onset of kinase resistance mutations. Angewandte Chemie. Doi.org/10.1002/anie.202200983.