Eleven years of cancer research has proven fruitful for a scientist at Johns Hopkins who uncovered a new tumor-suppressive response that could lead to novel therapies targeting hard-to-treat cancers.
The new study, funded in part by the National Institutes of Health and the National Cancer Institute, showed that targeting a key process of how cells make proteins can inhibit cancer cells—and resolves what makes them so sensitive.
The findings, published in the June 18, 2025 Cell Chemical Biology, open the door to potential new treatments for cancers with common genetic mutations.
The researchers found that using a drug to inhibit the enzyme responsible for human RNA (rRNA) transcription—called RNA Polymerase 1, or Pol 1—triggered a unique stress response that rewires splicing, or the way cancer cells produce forms of proteins, to ultimately suppress tumor growth.
“Ribosome biogenesis has long been known as a hallmark of cancer,” says study leader Marikki Laiho, M.D., Ph.D., a Johns Hopkins professor of radiation oncology in the Department of Radiation Oncology and Molecular Radiation Sciences.
In 2014, she and her team identified that Pol 1 is a meaningful therapeutic target in cancers. She began laboratory studies using human cell lines to study a small molecule, BMH-21, developed together with Johns Hopkins pharmacology and molecular sciences expert James Barrow, Ph.D., to inhibit the Pol 1 enzyme.
In the latest study, the team analyzed more than 300 cancer cell lines and found that tumors with certain mutations were especially sensitive to Pol 1 inhibitors, such as BMH-21—and a new drug, called BOB-42.
These alterations are common in cancers with mismatch repair deficiency (MMRd)—including colorectal, stomach and uterine cancers—which results in copying errors going uncorrected when DNA replicates and cells divide, causing high rates of additional mutations and cancer risk.
The team tested the new drug in animal models, and patient-derived tumors containing the same key genetic markers and recorded a significantly reduced tumor growth—by up to 77%—in melanoma and colorectal cancers.
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“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 Dr. Laiho, who holds patents on Pol 1 inhibitors that are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
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“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.”
“Targeting this pathway could not only suppress tumor growth but also modulate tumor antigenicity and enhance responsiveness to immunotherapies.”
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