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Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials

Use of high-quality tools is an essential element of Good Research Practice. Like for many other aspects, “high quality” is a relative term suggesting that the tools are fit-for-purpose according to the best information available today.
A recent paper by Lin and colleagues illustrates that, with the advancement of technologies, good knowledge may be replaced by better knowledge:
In this study, the authors used CRISPR gene editing techniques to examine the mechanisms of ten cancer drugs that target one of six proteins, which have been reported as important for the survival of cancer cells in over 180 publications. The drugs studied have been used in at least 29 different clinical trials involving a total of over 1,000 patients, and include prominent candidates such as citarinostat and ricolinostat, which are being tested against multiple myeloma.
Contrary to the previous reports based on RNA silencing, the drugs did not actually kill cancer cells by inhibiting their target proteins: they still worked when given to cells deficient in their target. Rather, the drugs induced cell death through off-target mechanisms.
Lin et al. argue that it will be necessary to adopt more rigorous validation approaches in preclinical trials to verify a causal link between target and disease and that future drug candidates work as intended.

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