These results are likely to improve the success rate of cancer drug development.
Almost 90% of medicines do not reach the market, highlighting the clear need for greater efficiency in drug development. The story is no different for drugs aimed at treating cancer, as many of them fail for various reasons. Now, researchers have revealed one reason some anti-cancer compounds cause unexpected side effects. This research can help guide understanding of why some drugs look more promising than others, providing a new tool that can be used to identify those drugs and drug candidates.
One of the most essential and energy-consuming cellular processes is ribosome biogenesis, which is the formation of the cellular machinery that makes all proteins. For cancer cells, this process is of utmost importance. A recent study published in the journal eLife From the Storrs Institute for Medical Research, it examined more than 1,000 existing anti-cancer drugs to assess how they affected the structure and function of the nucleus, the ubiquitous cellular organelle where ribosomes are made.
“All cells have to make proteins to function, so they have to make ribosomes, which are also protein complexes themselves,” said lead author Tamara Potapova, Ph.D., who specializes in research in the lab of researcher Jennifer Girton. “In cancer cells, ribosome production has to be overproduced to compensate for the higher proliferation rates which require more proteins.”
The nucleus is a special part of the cell nucleus that contains the ribosome DNAWhere is the ribosome RNA Production and assembly of ribosomes occurs largely. Nuclei can vary greatly in appearance, serving as visual indicators of the overall health of the process. Thus, the team found a way to take advantage of this difference and wondered how chemotherapy drugs could affect the nucleus, causing nuclear stress.
“In this study, we not only evaluated how anticancer drugs alter the appearance of nuclei, but we also identified classes of drugs that cause distinct nuclei morphologies,” said Girton. “This has enabled us to create a classification system for nuclei based on their appearance, a resource that other researchers can use.”
Because the hallmark of cancer is unchecked spread, most existing chemotherapy agents are designed to slow this spread. “The logic was to find out if, intentionally or unintentionally, these drugs affect ribosome biogenesis and to what degree,” Potapova said. “Hitting ribosome biogenesis can be a double-edged sword, as it impairs the viability of cancer cells while simultaneously altering protein production in normal cells.”
Different drugs affect different pathways involved in the growth of cancer. Those that affect ribosome production can induce distinct states of nuclear stress that manifest in easily visible morphological changes. However, nuclear stress can be difficult to measure.
“This was one of the problems that held this field back,” Potapova said. “Cells can have different numbers of nuclei of different sizes and shapes, and it has been difficult to find a single parameter that can fully describe a ‘normal’ nucleus. Developing this tool, which we called the Nuclear Normality Score, allowed us to measure stress nuclear stress accurately, and can be used by other laboratories to measure nuclear stress in their experimental models.
By comprehensively screening anticancer compounds on nuclear stress, the team identified one class of enzymes in particular, cyclin-dependent kinases, whose inhibition leads to almost complete destruction of the nucleus. Many of these inhibitors failed clinical trials, and their detrimental effect on the nucleus was not previously fully appreciated.
Drugs often fail clinical trials because of the excessive and unintended toxicity that can result from their off-target effects. This means that 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 organ.
“I hope at least that this study will raise awareness that some anti-cancer drugs can cause unintended disruption of the nucleus, which can be very salient,” Potapova said. “This possibility must be taken into account during the development of new drugs.”
Reference: “Characteristic Cases of Nuclear Stress Induced by Anticancer Drugs” by Tamara A. Potapova, and Jay R. Unruh, Juliana Conkright-Fincham, Charles A.S. Banks, Lawrence Florence, and David A. Schneider, and Jennifer L. Girton, July 13. 2023, eLife.
This work was funded by institutional support from the Storrs Institute for Medical Research.