The Babak Lab shared a post on LinkedIn:
“Scientific Wednesdays: Why Many Cancer Drugs Don’t Work the Way We Think
Disclaimer:
This is not a brand-new publication (Lin et al., Sci. Transl. Med., 2019), but the insights it offers remain the gold standard for understanding drug mechanisms in oncology today.
This study used CRISPR-Cas9 mutagenesis and genetic target-deconvolution to interrogate a set of cancer drugs and their purported targets in clinical testing. Contrary to prior assumptions based on biochemical data, the proteins these drugs were designed to hit are often non-essential for cancer cell proliferation.
Key Focus
The authors investigated why >90% of oncology drug–indication pairs fail in clinical development and whether assumed targets truly drive the drugs’ effects.
Key Insights
• The study revealed that 10 out of 10 tested drugs killed cancer cells via off-target toxicity, proving that the purported targets were non-essential for survival
• Genetic target-deconvolution revealed mischaracterization of drug mechanisms — e.g., the agent OTS964 actually targets CDK11 rather than its initially proposed target.
• This challenged the previously widespread reliance on biochemical potency and RNAi-based validation
Conclusion
To increase clinical success, we must validate targets genetically before entering trials. Relying solely on biochemical potency or RNAi is no longer enough.
Image generated using Sora by OpenAI.
A link to the full article can be found in the comments section.”
Maria (Masha) Babak, Head of The Babak Lab and Assistant Professor at City University of Hong Kong, shared this post:
“If genetics says “no” and biochemistry says “yes” – trust genetics.”
Title: Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials
Authors: Ann Lin, Christopher J Giuliano, Ann Palladino, Kristen M John, Connor Abramowicz, Monet Lou Yuan, Erin L Sausville, Devon A Lukow, Luwei Liu, Alexander R Chait, Zachary C Galluzzo, Clara Tucker, Jason M Sheltzer
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