Scientists have uncovered a new way to reprogram cancer cells by targeting a key protein-making enzyme, which disrupts tumor growth and opens a path to more precise treatments.
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.
The discovery shows that the production of ribosomal RNA (rRNA) is connected to how cells manage RNA splicing (a process that edits RNA). In studies of cancer cell lines using drugs that block rRNA production, a new stress response pathway was revealed. This pathway involves proteins called RPL22, RPL22L1, and MDM4. RPL22 plays a key role in controlling RNA splicing in coordination with rRNA production. Credit: Cell Chemical Biology
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.
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.”
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