ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways

Thuc M. Le, Soumya Poddar, Joseph R. Capri, Evan R. Abt, Woosuk Kim, Liu Wei, Nhu T. Uong, Chloe M. Cheng, Daniel Braas, Mina Nikanjam, Peter Rix, Daria Merkurjev, Jesse Zaretsky, Harley I. Kornblum, Antoni Ribas, Harvey R. Herschman, Julian Whitelegge, Kym F. Faull, Timothy R. Donahue, Johannes Czernin and Caius G. Radu ()
Additional contact information
Thuc M. Le: University of California, Los Angeles
Soumya Poddar: University of California, Los Angeles
Joseph R. Capri: University of California, Los Angeles
Evan R. Abt: University of California, Los Angeles
Woosuk Kim: University of California, Los Angeles
Liu Wei: University of California, Los Angeles
Nhu T. Uong: University of California, Los Angeles
Chloe M. Cheng: University of California, Los Angeles
Daniel Braas: University of California, Los Angeles
Mina Nikanjam: University of California, Los Angeles
Peter Rix: Vector Pharma Advisors Inc.
Daria Merkurjev: University of California, Los Angeles
Jesse Zaretsky: University of California, Los Angeles
Harley I. Kornblum: University of California, Los Angeles
Antoni Ribas: University of California, Los Angeles
Harvey R. Herschman: University of California, Los Angeles
Julian Whitelegge: University of California, Los Angeles
Kym F. Faull: University of California, Los Angeles
Timothy R. Donahue: University of California, Los Angeles
Johannes Czernin: University of California, Los Angeles
Caius G. Radu: University of California, Los Angeles

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms. Quantification of nucleotide biosynthesis in ATR-inhibited acute lymphoblastic leukemia (ALL) cells reveals substantial remaining de novo and salvage activities, and could not eliminate the disease in vivo. However, targeting these remaining activities with RNR and dCK inhibitors triggers lethal replication stress in vitro and long-term disease-free survival in mice with B-ALL, without detectable toxicity. Thus the functional interplay between alternative nucleotide biosynthetic routes and ATR provides therapeutic opportunities in leukemia and potentially other cancers.

Date: 2017
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DOI: 10.1038/s41467-017-00221-3

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