Data from Resilience and Vulnerabilities of Tumor Cells under Purine Shortage Stress

<div>AbstractPurpose:<p>Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.</p>Experimental Design:<p>Using the recently developed purine shortage–inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.</p>Results:<p>We demonstrate that when <i>de novo</i> purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multiprotein complexes of <i>de novo</i> 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 <i>de novo</i> 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 <i>in vivo</i>. 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.</p>Conclusions:<p>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.</p></div>