Researchers at the Johns Hopkins Kimmel Cancer Center and Department of Radiation Oncology and Molecular Radiation Sciences 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 published June 18 in Cell Chemical Biology , showed that targeting a key process of how cells make proteins can inhibit cancer cells and resolves what makes them so sensitive. The findings open the door to potential new treatments for cancers with common genetic mutations.
The researchers found that using a drug to inhibit RNA Polymerase 1 (Pol 1) — the enzyme responsible for human ribosomal RNA (rRNA) transcription — triggered a unique stress response that rewires splicing, or the way cancer cells produce forms of proteins, to ultimately suppress tumor growth. Ribosomal RNA genes are essential for building ribosomes, the machineries that translate proteins.
"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, Laiho and 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 Pol 1.
In the latest study, Laiho and team analyzed more than 300 cancer cell lines and found that tumors with mutations in RPL22 or high levels of MDM4 and RPL22L1 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. MMRd results in copying errors going uncorrected when DNA replicates and cells divide, causing high rates of additional mutations and an increased risk of developing cancer.
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."
In addition to Laiho, Barrow and Fan, other researchers on the study are Hester Liu, Gregory Stacheleck, Asma Begum, Catherine Davis, Tony Dorado, Glen Ernst, William Reinhold, Busra Ozbek, Angelo De Marzo and N.V. Rajeshkumer.
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.
Laiho holds patents on RNA polymerase 1 inhibitors, which are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
