Drug screening in human physiologic medium identifies uric acid as an inhibitor of rigosertib efficacy
Name
174329.2-20240909125339-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf
Description
Published version
Size
1.8 MB
Format
Adobe PDF
Checksum (MD5)
1e26244cd205d6e274080e41fb44c14a
Author(s)
Rawat, Vipin
DeLear, Patrick
Prashanth, Prarthana
Ozgurses, Mete Emir
Tebeje, Anteneh
Burns, Philippa A
Conger, Kelly O
Solís, Christopher
Hasnain, Yasir
Novikova, Anna
Date Issued
May 30, 2024
Journal
JCI Insight
Publisher
American Society for Clinical Investigation
Version
Final published version
Abstract
The nonphysiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels affect therapeutic response by performing drug screening in human plasma-like medium. We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds, including rigosertib, an experimental cancer therapeutic that recently failed in phase III clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism end product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. These results demonstrate the broad and dramatic effects nutrient levels can have on drug response and how incorporation of human-specific physiological nutrient medium might help identify compounds whose efficacy could be influenced in humans.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Terms of Use
Creative Commons Attribution
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DOI of Published Version
https://doi.org/10.1172/jci.insight.174329
