As more drug targets are discovered in the fight to treat diseases such as cancer, producing the right drugs for these targets is key to providing the best treatment and prolonging health in cancer patients.
However, FDA approval currently has a staggering 97% failure rate at clinical trials for oncology; typically, due to issues with drug efficacy or toxicity (Wong, Siah and Lo, 2019). One common issue is that several cancer drugs actually work via off-target effects, suggesting the original targets are nonessential for cancer cell survival. Failing to understand the mechanism of action (MOA) of such drugs can lead to:
- Mischaracterization of target-specific inhibitors
- Misidentification of biomarkers (by being unable to decipher the drug’s true target)
- Interlaboratory variability between cell lines without reasonable cause
A study by Lin et al. (2019) produced knock-out clones in three cancer cell lines, and performed CRISPR competition assays in 32 cell lines as well as CRISPRi-knockdown competition assays in another four cell lines. It showed that HDAC6, MAPK14, PAK4, PBK, and PIM1*, which were previously thought to be essential proteins for cancer are, in fact, nonessential for cancer cell survival.
Off-target effects are common for small molecule drugs and we expect minor side effects with most. Yet, in many cancer trials, it seems the off-target interactions are actually the MOA through which the drug works to block cancer progression. This is a common problem to affect cancer trials.
For example, research into the maternal embryonic leucine zipper kinase (MELK) showed that it’s small molecule inhibitor, OST167, is able to kill MELK knockout cancer cells (Giuliano et al., 2018). This suggests that MELK is dispensable for cancer cell fitness, despite it being previously identified as crucial in multiple cancer types.
Failing to recognize the off-target effects causes the mischaracterization of target-specific inhibitors and, therefore, likely contributes to the low FDA approval rate.
A drug’s true target
Our lack of understanding of a drug’s MOA hinders efforts in uncovering biomarkers capable of predicting therapeutic responses, further highlighting the importance of understanding drug-target interaction.
Protein interaction analysis is a vital preclinical research necessity and being provided with the right equipment for precise, reliable and informative results is a sure way to evolving our understanding of drug MOA. Chief Executive Officer of Fluidic Analytics, Andrew Lynn, states he wants their cutting-edge technology in protein analysis to “advance [into] a number of high-potential clinical applications that could help us make an even bigger impact on the world”.
- Some key drug targets, which were previously thought to be essential for cancer have been shown to be dispensable for cancer cell survival
- The MOA of some well-known cancer drugs has been shown to be through off-target interactions
- Using more accurate and stringent protein interaction studies can help to confirm drug MOA early, thereby improving the low FDA approval rate
- A better and earlier understanding of protein interactions in oncology is vital for continuing cancer research and improving treatment, something which Fluidic Analytics has made great strides in – creating novel technology that accurately analyses even challenging protein interactions
1. Wong, C., Siah, K. and Lo, A. (2018). Corrigendum: Estimation of clinical trial success rates and related parameters. Biostatistics, 20(2), pp.273-286.
2. Lin, A., Giuliano, C., Palladino, A., John, K., Abramowicz, C., Yuan, M., Sausville, E., Lukow, D., Liu, L., Chait, A., Galluzzo, Z., Tucker, C. and Sheltzer, J. (2019). Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translational Medicine, 11(509), p.eaaw8412.
3. Giuliano, C., Lin, A., Smith, J., Palladino, A. and Sheltzer, J. (2018). MELK expression correlates with tumor mitotic activity but is not required for cancer growth. eLife, 7.
*HDAC6 – Histone deacetylase 6, Mitogen-Activated Protein Kinase 14 – MAPK14, p21-Activated kinase 4 – PAK4, Lymphokine-activated killer T-cell-originated protein kinase (PBK), Proto-oncogene serine/threonine-protein kinase – PIM1