Why some cancer drugs have unexpected side effects

Researchers have revealed one reason why certain anti-cancer compounds can cause unexpected side effects, which could help guide an understanding of why some drugs show more promise than others, and provide a new tool to be used to identify those drugs and other possible candidates.

One of the most 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, reports News Medical.

A recent study published online in eLife – from the Stowers Institute for Medical Research – screened more than 1 000 existing anti-cancer drugs to assess how they affect the structure and function of the nucleolus, the ubiquitous cellular organelle where ribosomes are made.

“All cells must make proteins to function, so they have to make ribosomes, which are also protein complexes themselves. In cancer cells, ribosome production must be in overdrive to compensate for high proliferation rates requiring even more proteins,” said Tamara Potapova, Ph.D, lead author and research specialist in the lab of investigator Jennifer Gerton, Ph.D.

The nucleolus is a special 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 overall health of this process. Thus, the team found a way to capitalise on this variation and asked how chemotherapy drugs impact the nucleolus, causing nucleolar stress.

“In this study, we not only evaluated how anti-cancer drugs alter the appearance of nucleoli, but also identified categories of drugs that cause distinct nucleolar shapes,” said Gerton. “This enabled us to create a classification system for nucleoli based on their appearance – which is 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 be a double-edged sword – it would impair the viability of cancer cells while simultaneously altering protein production in normal cells.”

Different drugs have impacts on different pathways involved in cancer growth. Those that influence ribosome production can induce distinct states of nucleolar stress that manifest in easily seen morphological changes. However, nucleolar stress can be difficult to measure.

“This was one of the issues impeding this field,” said Potapova. “Cells can have different numbers of nucleoli with various sizes and shapes, so it’s been challenging to find a single parameter that can fully describe a ‘normal’ nucleolus.

“Developing this tool, that we termed ‘nucleolar normality score’, allowed us to measure nucleolar stress precisely, and can be used by other labs to measure nucleolar stress in their experimental models.”

Through the comprehensive screening of anti-cancer compounds on nucleolar stress, the team identified one class of enzymes in particular, cyclin-dependent kinases, whose inhibition destroys the nucleolus almost completely.

Many 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 due to excessive and unintended toxicity that can be caused by their off-target effects. This means a molecule designed to target one pathway may also affect a different pathway or inhibit an enzyme required for cellular function. In this study, the team found an effect on an entire organelle.

Study details

Distinct states of nucleolar stress induced by anti-cancer drugs

Tamara Potapova, Jay Unruh, Juliana Conkright-Fincham, Charles Banks, Laurence Florens, David Schneider, Jennifer Gerton.

Published in eLife on 23 July 2023

Abstract

Ribosome biogenesis is one of the most essential and energy-consuming cellular functions. It takes place mainly in the nucleolus. For cancer cells, the nucleolar function is especially important due to the high demand for ribosomes to support continuous proliferation. The goal of this study was to assess the effects of existing chemotherapy drugs on the nucleolar state. For this, we conducted an imaging-based screen for anticancer drugs that induce morphological re-organisation consistent with nucleolar stress. For a readout, we developed a novel parameter termed ‘nucleolar normality score’, which measures ratios of dense fibrillar center and granular component in the nucleolus and nucleoplasm. We show that multiple classes of drugs cause nucleolar stress, including DNA intercalators, inhibitors of mTOR/PI3K, heat shock proteins, proteasome, and cyclin-dependent kinases (CDKs). Different classes of drugs induced morphologically and molecularly distinct states of nucleolar stress. By applying phospho-proteomics and live imaging strategies, we characterized in detail the nucleolar stress induced by inhibition of transcriptional CDKs, particularly CDK9, the main CDK that targets RNA Pol II. Inhibition of CDK9 dramatically reduced rRNA production, caused dissociation of RNA Polymerase I catalytic subunit POLR1A from ribosomal DNA and dispersal of the nucleolar granular component, a stress we refer to as the “bare scaffold” state. We identified multiple nucleolar CDK phosphorylation substrates, including RNA Pol I – associated protein Treacle, and demonstrated that CDK9 can phosphorylate Treacle in vitro. This implies that transcriptional CDKs coordinate the action of RNA pol I and RNA pol II. Furthermore, molecular dynamics analysis of the endogenous nucleolar protein NPM1 demonstrated that CDK inhibition vastly increased its mobility, consistent with the loss of nucleolar integrity. We conclude that many classes of chemotherapy compounds directly or indirectly target nucleolar structure and function, and recommend considering this in anticancer drug development.

eLife article – Distinct states of nucleolar stress induced by anti-cancer drugs (Open access)

News Medical article – Stowers researchers reveal why certain anti-cancer drugs can cause unexpected side effects (Open access)

See more from MedicalBrief archives:

SA cancer rates set to double by 2030, actuaries predict

No association between price and efficacy of cancer drugs — four-nation study

Most new cancer drugs don’t work — 5-year European study

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