Language
English
Publication Date
10-15-2025
Journal
Clinical Cancer Research
DOI
10.1158/1078-0432.CCR-25-1667
PMID
40788171
PMCID
PMC12399269
PubMedCentral® Posted Date
9-1-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Purpose: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.
Experimental design: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.
Results: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multiprotein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. Although this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit methylthioadenosine phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced antitumor immunity.
Conclusions: Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.
Keywords
Humans, Purines, Animals, Mice, Cell Line, Tumor, Male, Xenograft Model Antitumor Assays, Purine-Nucleoside Phosphorylase, Neoplasms, Microtubules, Docetaxel
Published Open-Access
yes
Recommended Citation
Yu, Jianpeng; Jin, Chen; Su, Cheng; et al., "Resilience and Vulnerabilities of Tumor Cells under Purine Shortage Stress" (2025). Faculty and Staff Publications. 4913.
https://digitalcommons.library.tmc.edu/baylor_docs/4913
Included in
Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Specialties Commons, Microbiology Commons