Stowers researchers reveal why certain anti-cancer drugs could cause unexpected unintended effects

With around 90% of medication failing to make it to market, the potential for improving efficiency throughout the drug development industry is obvious. Drugs designed to combat cancers suffer similar rates of failure for a lot of reasons. Now, researchers have revealed one reason why certain anti-cancer compounds could cause unexpected unintended effects. This research could help guide an understanding of why some drugs show more promise than others, providing a brand new tool that will be used to discover those drugs and drug candidates.

Some of the essential and energy-consuming cellular processes is ribosome biogenesis, the formation of the cellular machines that manufacture all proteins. For cancer cells, this process is paramount. A recent study published online in eLife on July 13, 2023, from the Stowers Institute for Medical Research screened over 1,000 existing anti-cancer drugs to evaluate how they impact the structure and performance of the nucleolus, the ever-present cellular organelle where ribosomes are made.

All cells must make proteins to operate, in order that they must make ribosomes, that are also protein complexes themselves. In cancer cells, ribosome production should be in overdrive to compensate for prime proliferation rates requiring much more proteins.”

Tamara Potapova, Ph.D.,  lead writer, research specialist within the lab of Investigator Jennifer Gerton, Ph.D.

The nucleolus is a special a part of the cell nucleus that houses ribosomal DNA, and where ribosomal RNA production and ribosome assembly largely takes place. Nucleoli can vary greatly in appearance, serving as visual indicators of the general health of this process. Thus, the team found a strategy to capitalize on this variation and asked how chemotherapy drugs impact the nucleolus, causing nucleolar stress.

“On this study, we not only evaluated how anti-cancer drugs alter the looks of nucleoli, but additionally identified categories of medication that cause distinct nucleolar shapes,” said Gerton. “This enabled us to create a classification system for nucleoli based on their appearance that may be a resource other researchers can use.”

Because cancer’s hallmark is unchecked proliferation, most existing chemotherapeutic agents are designed to slow this down. “The logic was to see whether these drugs, intentionally or unintentionally, are affecting ribosome biogenesis and to what degree,” said Potapova. “Hitting ribosome biogenesis could possibly be a double-edged sword-;it will impair the viability of cancer cells while concurrently altering protein production in normal cells.”

Different drugs impact different pathways involved in cancer growth. People who influence ribosome production can induce distinct states of nucleolar stress that manifest in easily seen morphological changes. Nonetheless, nucleolar stress will be difficult to measure.

“This was considered one of the problems that impeded this field,” said Potapova. “Cells can have different numbers of nucleoli with different configurations and dimensions, and it has been difficult to seek out a single parameter that may fully describe a “normal” nucleolus. Developing this tool, that we termed “nucleolar normality rating,” allowed us to measure nucleolar stress precisely, and it may possibly be utilized by other labs to measure nucleolar stress of their experimental models.”

Through the great screening of anti-cancer compounds on nucleolar stress, the team identified one class of enzymes particularly, cyclin-dependent kinases, whose inhibition destroys the nucleolus almost completely. A lot of these inhibitors failed in clinical trials, and their detrimental impact on the nucleolus was not fully appreciated previously.

Drugs often fail in clinical trials as a result of excessive and unintended toxicity that will be attributable to their off-target effects. Because of this a molecule designed to focus on one pathway might also be impacting a special pathway or inhibiting an enzyme required for cellular function. On this study, the team found an effect on a whole organelle.

“I hope at a minimum this study increases awareness that some anti-cancer drugs could cause unintended disruption of the nucleolus, which will be very distinguished,” said Potapova. “This possibility needs to be considered during recent drug development.”

Additional authors include Jay Unruh, Ph.D., Juliana Conkright-Fincham, Ph.D., Charles A. S. Banks, Ph.D., Laurence Florens, Ph.D., and David Schneider, Ph.D.

This work was funded by institutional support from the Stowers Institute for Medical Research.