Xia Gao

Supplementary Figures and Tables: 5 figures, 3 tables

A graphical abstract summarizing tumor cells’ strategies for adapting to and their vulnerabilities under purine shortage stress.

The MTAP-dependent purine salvage is a source of purine supply for cancer cells.

Treating tumor-bearing mice with DRP-104 in combination with MTDIA does not affect animal’s body weight but alters the tumor’s immune microenvironment.

Supplementary Table 1. Metabolite profiling of C4-2 and PC3 cells (LC-MS profiling results normalzied by cell confluency).

DRP-104 simulates DNA damage and the cGAS-STING pathway.

DON inhibits FGAMS, a de novo purine biosynthesis enzyme, with the lowest Ki.

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.

DRP-104 affects purine metabolism and purine supply.