The de novo purine synthesis pathway is an established therapeutic vulnerability in small cell lung cancer (SCLC) and other tumor types. However, crosstalk between de novo purine synthesis and purine salvage—a second purine synthesis pathway—and corresponding therapeutic implications remain poorly defined. In their study, Tabata and colleagues observed expression of hypoxanthine phosphoribosyltransferase 1 (HPRT1), a rate-limiting enzyme in the purine salvage pathway, in SCLC samples and cell lines using immunohistochemistry and Western blotting, respectively. By eliminating HPRT1 expression using CRISPR-Cas9 in SCLC cell lines and treating them with a pharmacologic de novo purine synthesis inhibitor, the authors showed that purine salvage abrogation increased SCLC cell sensitivity to de novo purine synthesis inhibition. Similar findings were recapitulated with HPRT1-deficient xenografts in a mouse model. Metabolomic and isotope tracing experiments demonstrated that HPRT1 depletion increased abundances of de novo purine synthesis pathway metabolic intermediates. In sum, this study implicates purine salvage...

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