Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions

by Selleckchem | Dec 03 2023

Chemical screening studies have identified drug sensitivities across hundreds of cancer cell lines but most putative therapeutics fail to translate. Discovery and development of drug candidates in models that more accurately reflect nutrient availability in human biofluids may help in addressing this major challenge. Here we performed high-throughput screens in conventional versus Human Plasma-Like Medium (HPLM). Sets of conditional anticancer compounds span phases of clinical development and include non-oncology drugs. Among these, we characterize a unique dual-mechanism of action for brivudine, an agent otherwise approved for antiviral treatment. Using an integrative approach, we find that brivudine affects two independent targets in folate metabolism. We also traced conditional phenotypes for several drugs to the availability of nucleotide salvage pathway substrates and verified others for compounds that seemingly elicit off-target anticancer effects. Our findings establish generalizable strategies for exploiting conditional lethality in HPLM to reveal therapeutic candidates and mechanisms of action.

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The passage you provided describes a research study that involves screening potential drug candidates in cancer cell lines using two different culture media: conventional culture medium and Human Plasma-Like Medium (HPLM). The study aims to address the challenge of translating drug sensitivities observed in cell line studies into effective cancer treatments.

In this study, various compounds, including both anticancer and non-oncology drugs, were tested in both conventional medium and HPLM. One of the key findings of the research was the discovery of a unique dual mechanism of action for brivudine, a drug approved for antiviral treatment. The researchers found that brivudine affects two independent targets in folate metabolism, which is crucial for cell growth and proliferation. This dual mechanism of action suggests that brivudine may have potential as an anticancer agent, in addition to its antiviral properties.

Furthermore, the study identified other drugs whose effectiveness was influenced by the availability of nucleotide salvage pathway substrates. This information is important because it helps researchers understand the specific conditions under which these drugs can effectively target cancer cells. Additionally, the study verified certain compounds that appeared to have off-target anticancer effects, indicating that their mechanisms of action extend beyond their originally intended purposes.

Overall, the research provides valuable insights into the conditional lethality of drugs in HPLM, shedding light on potential therapeutic candidates and the underlying mechanisms of their actions. This knowledge can guide future drug development efforts and enhance our understanding of how different compounds interact with cancer cells under specific nutrient availability conditions.