Cryo-electron microscopy (cryo-EM) continues to revolutionize our understanding of cancer. Over the past several years, scientists have used cryo-EM to uncover new cancer pathways, enabling them to obtain an atomic-level description of key cancer protein targets and a framework for improving pharmaceutical interventions. In the past year alone, this method has led to some impressive cancer cell research breakthroughs.
Cryo-EM protein structure research uncovers new insights into prostate cancer
One area in which cryo-EM has made substantial progress in 2022 is prostate cancer, the second commonly occurring cancer in men accounting for 1.4 million new cases globally in 2020. In a study published in Molecular Cell in April 2022 and led by a team at the Memorial Sloan Kettering Cancer Center, researchers used cryo-EM to uncover new details about how the androgen receptor, a key player in the progression of prostate cancer, actually causes the disease.
Using cryo-EM, the researchers were able to view novel structural details of the androgen receptor, identifying unique features that separate it from other hormone receptors. The cryo-EM images revealed that the androgen receptor can form different DNA-binding shapes, allowing it to turn on a wide range of genes depending on the conformation it is in. These different three-dimensional shapes enable the androgen receptor to interact with other proteins that change its shape such as ERG, a main driver of prostate cancer.
The researchers hope to use cryo-EM to continue to view the androgen receptor in more detail. Eventually, the goal is to design drugs that block specific movements of the androgen receptor—for example, by prohibiting it from interacting with ERG.
New cryo-EM cancer cell research may help combat leukemia
Over the past year, cryo-EM also helped to advance our understanding of leukemia. Acute myeloid leukemia (AML), a cancer that starts in the bone marrow and moves quickly into a person’s blood, is one of the most common types of leukemia in adults, accounting for 1% of all cancers. While scientists have achieved numerous high-resolution structures of macromolecules using cryo-EM, the technique had been difficult to apply to specimens smaller than 30 kilodaltons (kDa), leading to some big gaps in structural biology.
Using an experimental approach, a group of researchers used cryo-EM to determine the structure of the 11 kDA KIX domain of CREB-binding protein, a potential therapeutic target for acute myeloid leukemia and other cancers. Source: Cryo-EM, Protein Engineering, and Simulation Enable the Development of Peptide Therapeutics against Acute Myeloid Leukemia
To overcome this limitation, a group of researchers at the University of Science and Technology of China, The University of Tsukuba, and Stanford University came up with an experimental approach that involved sandwiching the KIX domain between an inner and outer shell to stabilize it. Their solution, published in February 2022 in ACS Central Science, allowed them to determine the structure of the 11 kDA KIX domain of CREB-binding protein, a potential therapeutic target for AML and other cancers that has defied structure-based inhibitor design.
Using this double-shell design, not only were the researchers able to obtain a cryo-EM structure at 2.6 Angstrom resolution, but they added in other molecules to see if these molecules might bind to the KIX domain and inhibit its function. The ability to see how the KIX domain binds in near atomic-level detail may eventually provide a strategy for the development of next-generation inhibitors. In addition, this experimental cryo-EM cancer cell research approach will likely be applied to the study of other difficult-to-image proteins, including some viral proteins.
Enabling drug discovery with complete cryo-EM protein structure of Janus kinase
Thanks to continued cryo-EM cancer cell research, scientists recently obtained the full-length structure of Janus kinase, a critical signaling molecule in cells. For years, scientists have known that Janus kinase can cause certain types of cancer when they malfunction. While drugs exist that block these kinases, they were developed without knowing the structure—in effect, causing side effects by blocking both healthy and mutated Janus kinases.
After more than two decades of effort, researchers at Stanford University were able to obtain the complete structure of a Janus kinase as well as the mechanism for how these kinases work. These results, which were published in Science in March 2022, could pave the way to new and better drugs for certain types of cancers.
Continual cryo-EM breakthroughs in breast cancer research
These are just a few recent examples of the ways in which cryo-EM is advancing cancer research. These studies come in addition to ongoing uses of cryo-EM in structural oncology to accelerate breast cancer research. For example, Prof. Deb Kelly and a team of researchers at Pennsylvania State University are employing cryo-EM to visualize cancer-related proteins, including BRCA1 and p53, with the goal of understanding what structural changes lead to their malfunction. Ultimately, the hope is that these insights will inform the development of highly targeted drug treatments.
As cryo-EM continues to improve, researchers are finding ways to apply the technique to a wider range of protein structures needed to understand the conditions for cancer cell growth and identify new ways to treat cancer.
To learn more about the role of cryo-EM in cancer cell research, please download our eBook, “Understanding the Complexity of Cancer with Cryo-EM.”
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