A new study reveals that blocking ribosomal RNA production rewires cancer cell behavior and could help treat genetically unstable tumors.
Researchers at the Johns Hopkins Kimmel Cancer Center and the Department of Radiation Oncology and Molecular Radiation Sciences have identified a tumor-suppressive response that could lead to new treatments for cancers that are difficult to treat.
In a study published June 18 in Cell Chemical Biology and partially funded by the National Institutes of Health, the team showed that interfering with a key step in protein production can inhibit cancer cell growth. The research also explains why certain cancer cells are particularly sensitive to this approach. These findings point to new therapeutic strategies for cancers with common genetic mutations.
The team discovered that blocking RNA Polymerase 1 (Pol 1), the enzyme responsible for transcribing human ribosomal RNA (rRNA), triggers a unique stress response. This response alters RNA splicing—the process by which cells generate different forms of proteins—and leads to tumor suppression. Ribosomal RNA genes are crucial for building ribosomes, the cellular machinery responsible for translating proteins.
A surprising role for RPL22 in RNA splicing
"Ribosome biogenesis has long been known as a hallmark of cancer," says study leader Marikki Laiho, M.D., Ph.D., the Willard and Lillian Hackerman Professor of Radiation Oncology and Vice Chair for Research of the Department of Radiation Oncology and Molecular Radiation Sciences. "Our study reveals that the ribosomal protein RPL22, typically a structural component of the ribosome, plays an unexpected dual role as a critical regulator of RNA splicing."
In 2014, Marikki Laiho and her team identified RNA Polymerase 1 (Pol 1) as a promising therapeutic target for cancer treatment. She began laboratory research using human cell lines to test a small molecule called BMH-21. This compound was developed in collaboration with James Barrow, Ph.D., a pharmacology and molecular sciences expert at Johns Hopkins, to block Pol 1 activity.
In their most recent study, the team examined more than 300 cancer cell lines and found that tumors with mutations in the gene RPL22, or with elevated levels of MDM4 and RPL22L1, were especially responsive to Pol 1 inhibitors like BMH-21 and a newly developed drug called BOB-42. These genetic changes are frequently found in cancers with mismatch repair deficiency, or MMRd, including colorectal, stomach, and uterine cancers. MMRd allows copying errors in DNA to go uncorrected during cell division, leading to a high number of mutations and a greater risk of cancer development.
Promising drug trial results in animals
The team tested the Pol 1 inhibitor BOB-42 in animal models, including patient-derived tumors containing the same key genetic markers. The drug reduced tumor growth by up to 77% in melanoma and colorectal cancers.
"These findings highlight a promising new path for targeting cancers, especially for patients with mismatch repair-deficient cancers that are resistant to existing therapies," says the study's first author, Wenjun Fan, Ph.D., research associate.
The study also suggests that changing how cancer cells splice RNA, or produce different forms of proteins, could affect how the immune system recognizes tumors. Combining immunotherapies with Pol 1 inhibitors may improve the effectiveness of immunotherapies.
"This is an entirely new conceptual framework for understanding how rRNA synthesis influences cancer cell behavior," says Laiho. "Targeting this pathway could not only suppress tumor growth but also modulate tumor antigenicity and enhance responsiveness to immunotherapies."
Reference: "Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22" by Wenjun Fan, Hester Liu, Gregory C. Stachelek, Asma Begum, Catherine E. Davis, Tony E. Dorado, Glen Ernst, William C. Reinhold, Busra Ozbek, Qizhi Zheng, Angelo M. De Marzo, N.V. Rajeshkumar, James C. Barrow and Marikki Laiho, 18 June 2025, Cell Chemical Biology.
DOI: 10.1016/j.chembiol.2025.05.012
The research was funded by grants from the National Institutes of Health (R01 GM121404 and P30 CA006973), the National Cancer Institute (K99 CA279786), Blue One Biosciences LLC, Commonwealth Foundation, Mary Kay Ash Charitable Foundation, Academy of Finland (288364), Maryland Cigarette Restitution Fund, and Harrington Scholar-Q9 Innovator Award.
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