Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine triphosphate (dCTP) can be produced by the de novo pathway (DNP) via ribonucleotide reductase, and/or by the nucleoside salvage pathway (NSP) via deoxycytidine kinase (dCK). The NSP's role in supporting tumor DNA replication is unknown. Here we show that survival of acute lymphoblastic leukemia cells upon inhibition of DNP-dependent dCTP production requires a functional NSP. Thus, DNP inhibition triggers a compensatory switch to NSP-mediated dCTP production. This metabolic switch can be imaged by positron emission tomography, thereby providing a non-invasive method for monitoring pharmacological targeting of the DNP. Blocking both DNP dCTP production using thymidine and the switch to NSP using a new dCK inhibitor induces replication stress overload and synthetic lethality in leukemia cells, without significant host toxicity. This co-targeting therapy may be broadly applicable against other malignancies characterized by high levels of replication stress.

Citation Format: Caius G. Radu, David A. Nathanson, Johannes Czernin. Co-targeting of convergent, switchable nucleotide biosynthetic pathways induces synthetic lethality in leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5097. doi:10.1158/1538-7445.AM2014-5097