Genetic approach corrects wrong notions about 10 cancer drugs
Genetic modifications are often used to verify the mechanisms of drugs. To a surprise of scientists, 10 cancer drugs miss their intended targets. Those molecules are still effective but appear to work with different proteins.
Pharmacology heavily relies on so-called targets. Most drugs intend to change the function of a molecule or a group of molecules. This specificity stems from initial biological studies, which can be less strict than pharmacological-grade analyses. As a cautionary example, the RNA interference method suggested MELK protein as an anti-cancer target. However, substances inhibiting MELK were still functioning, even in the absence of MELK protein.
Work with MELK inspired further research. Scientists from Cold Spring Harbor Laboratory tested whether 6 proteins (CASP3, HDAC6, MAPK14, PAK4, PBK, PIM1) are really targeted by their corresponding drugs (1541B, PAC-1, Citarinostat, Ricolinostat, Ralimetinib, SCIO-469, PF-03758309, OTS514, OTS964, SGI-1776). Currently, they are used in 29 clinical trials.
Cancer cells were modified with various CRISPR methods to stop the production of tested proteins. If the drugs were targeting them, cancer cells should be still viable after treatment. However, all tested compounds still killed modified cells. That observation could be explained only by off-targeting.
Researchers went on to decipher the true target of a single drug: OTS964. Instead of targeting PBK, it was found to target protein CDK11 (which has a different role in cancer disease). Drug manufacturer, OncoTherapy Science, did not comment on the finding.
More broadly, our results underscore the power of genetic approaches to improve the preclinical characterization of cancer drugs and drug targets.https://doi.org/10.1126/scitranslmed.aaw8412