In a new study, researchers from St. Jude Children's Research Hospital in the United States visually observed the structure of previously unknown ABL kinase, thereby providing new insights for the design of targeted therapies for adult and childhood cancer patients. This research will advance the understanding of drug resistance produced by cancer-targeted drugs. The relevant research results were published online in the Journal of Science.
The core of this achievement is the most powerful nuclear magnetic resonance (NMR) spectrometer in the United States, which was installed at St. Jude’s Children’s Research Hospital in 2019. Just as a microscope allows scientists to peek inside cells, NMR spectrometers allow people to visualize previously invisible or undetectable molecular structures that could not be observed with other technologies.
Dr. Charalampos Babis Kalodimos, co-corresponding author of the paper and director of the Department of Structural Biology at St. Jude’s Children’s Research Hospital, said, “This is the first time that protein kinases have been captured in such a short-lived conformation. Considering that there are more than 500 kinases in humans, this really shows that there are still many unknown areas to explore. People have been studying ABL kinase and its resistance mechanism for 20 years, but with this technology, we are now at a new starting point to improve targeted therapy.”
The fusion of the BCR and ABL genes promotes cell growth in several cancer types, the most obvious of which is chronic myelogenous leukemia (CML). The first widely used targeted drug interferes with the ABL kinase to block the activity of the BCR-ABL gene fusion. The drug imatinib has achieved significant success in adult CML and is sometimes used to treat childhood acute lymphoblastic leukemia (ALL). However, leukemia cells are often resistant to drugs targeting BCR-ABL, and the therapeutic effect is poor. Drug resistance is also a common phenomenon in other targeted drugs.
Dr. Charles W.M. Roberts, director of the Comprehensive Cancer Center at St. Jude’s Children’s Research Hospital, said, “Targeted drugs have shown significant responses in adults and children with cancer. Their cancer is driven by specific genetic events like the BCR-ABL gene fusion. However, we know that these drugs usually only work for a period of time before resistance develops. This discovery helps us understand how this resistance occurs and provides information that can design better drugs.”
These researchers used NMR spectroscopy to study the structure of ABL kinase and learn more about how resistance occurs. They visualized the previously unknown shape of ABL kinase and how the protein changed from an active state to an inactive state. Their study showed that the short-lived conformation of ABL kinase appeared only 5% of the time.
These conformations play an important role in how the ABL kinase is activated, and can be hijacked by mutations to convert the gene encoding this kinase into an oncogene. By studying the transient structure of ABL kinase when combined with the targeted inhibitor imatinib, these researchers have learned more about how resistance to this drug occurs. These findings provide new insights into how different states of this kinase (including inactive states) can be used to design more selective and potentially effective inhibitors.
Dr. Tao Xie, co-corresponding author of the paper and the Department of Structural Biology, St. Jude Children’s Research Hospital, said, “By elucidating the basic mechanism of drug resistance to ABL kinase-targeted drugs, we have shown that NMR spectroscopy can better understand other kinases and the potential of protein dynamics. In the dynamic changes of proteins, the biologically important conformations only appear in a short time. "