Resilience and Vulnerabilities of Tumor Cells under Purine Shortage Stress

作者：Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael A. Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomingerel Tserentsoodol, Michelle Bowie, Christopher J. Pirozzi, Daniel J. George, Robert Wild, Xia Gao, David M. Ashley, Yiping He, Jiaoti Huang · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-1667 · 被引用次数：6 · 研究领域：Biochemical and Molecular Research、interferon and immune responses、RNA modifications and cancer

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...