By Andrew K Lynn, CEO of Fluidic Analytics
In a recent paper in Science Translational Medicine, Lin et al. report that ten anticancer treatments they tested appear not to work via the mechanism of action originally thought (1). These findings indicate serious deficiencies in current methods for testing protein-drug interactions.
The authors have shown through CRISPR-Cas9 mutagenesis that—contrary to previous reports—the proteins targeted by all ten of the drugs were not essential for cancer proliferation. Furthermore, the efficacy of every drug tested was unaffected by the loss of its supposed target, which suggests that the drug compounds must be killing cancer cells via off-target binding.
Lin et al. report that they generated knock-out clones in at least three cancer cell lines, performed CRISPR competition assays in 32 cell lines, and performed CRISPRi-knockdown competition assays in an additional four cell lines. All these investigations consistently demonstrated that, contrary to the literature, the assumed cancer cell targets (including MELK, HDAC6, MAPK14, PAK4, PBK, and PIM1) are dispensable for cancer cell fitness.
The authors also report that a staggering 97% of drug indication pairs tested in oncological clinical trials fail to receive FDA approval (1). In most cases problems with efficacy or toxicity are cited as the reasons for failure.
It is generally known that small molecules can exhibit off-target effects that may confound the design of specific chemical inhibitors. The authors’ data suggest that rather than simply being the side effect of a drug, these off-target interactions are frequently the mechanism by which small molecules block cancer growth. It is unlikely that failure to identify off-target protein-drug interactions occurs only in development of anticancer drugs. Research into treatment of diverse diseases is almost certainly hampered by a lack of reliable tools that allow scientists to properly understand protein-drug interactions and identify drug targets.
As Jason Sheltzer, head of the lab that produced the Lin paper, explained to The New York Times: “A lot of the drug targets that are in clinical trials today were discovered with the best technology from five or 10 years ago” (2).
Lin’s study highlights how poorly we understand the mechanism of action of existing, supposedly well-characterized drugs. But the problem is about to become even more acute as research expands into difficult diseases like Alzheimer's disease. This will also be a problem when new drugs that interact with notoriously difficult targets, such as membrane proteins or intrinsically disordered proteins, come to market. One approach to overcoming these hurdles lies in the emergence of new technologies to help researchers model protein interactions more accurately.
Fluidic Analytics was founded by scientists whose wish to understand how proteins behave was frustrated by a lack of reliable tools. One of the tools we have developed, the Fluidity One-W, has contributed significantly to award-winning research by Professor Sara Linse into the mechanism by which several Alzheimer’s drugs bind to very challenging targets. Our vision as a company is to contribute to such transformative understanding, which could provide key insights into development of treatments for diseases like Alzheimer's.
- Lin, A., Giuliano, C.J., Palladino, A., John, K.M., Abramowicz, C., Yuan, M.L., Sausville, E.L., Lukow, D.A., Liu, L., Chait, A.R. and Galluzzo, Z.C., (2019). Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science translational medicine, 11(509), 8412.
- Zimmer, C. (2019) ‘Why aren’t cancer drugs better? The targets might be wrong’, The New York Times, 11 September, p.3.