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

Le, Thuc M.; Poddar, Soumya; Capri, Joseph R.; Abt, Evan R.; Kim, Woosuk; Wei, Liu; Uong, Nhu T.; Cheng, Chloe M.; Braas, Daniel; Nikanjam, Mina; Rix, Peter; Merkurjev, Daria; Zaretsky, Jesse; Kornblum, Harley I.; Ribas, Antoni; Herschman, Harvey R.; Whitelegge, Julian; Faull, Kym F.; Donahue, Timothy R.; Czernin, Johannes; Radu, Caius G.

doi:10.1038/s41467-017-00221-3

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

Journal Article · Mon Aug 14 00:00:00 EDT 2017 · Nature Communications

DOI:https://doi.org/10.1038/s41467-017-00221-3· OSTI ID:1425368

Le, Thuc M. ^[1]; Poddar, Soumya ^[1]; Capri, Joseph R. ^[1]; Abt, Evan R. ^[1]; Kim, Woosuk ^[1]; Wei, Liu ^[1]; Uong, Nhu T. ^[1]; Cheng, Chloe M. ^[1]; Braas, Daniel ^[2]; Nikanjam, Mina ^[3]; Rix, Peter ^[4]; Merkurjev, Daria ^[5]; Zaretsky, Jesse ^[2]; Kornblum, Harley I. ^[6]; Ribas, Antoni ^[7]; Herschman, Harvey R. ^[8]; Whitelegge, Julian ^[9]; Faull, Kym F. ^[10]; Donahue, Timothy R. ^[11]; Czernin, Johannes ^[12] more »

Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division
Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Metabolomic Center and David Geffen School of Medicine
Univ. of California, Los Angeles, CA (United States). Division of Hematology-Oncology
Vector Pharma Advisors Inc., San Diego, CA (United States)
Univ. of California, Los Angeles, CA (United States). Dept. of Microbiology, Immunology & Molecular Genetics
Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Dept. of Psychiatry and Biobehavioral Sciences and Semel Inst. for Neuroscience and Human Behavior and Jonsson Comprehensive Cancer Center and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and David Geffen School of Medicine and Division of Hematology-Oncology and Jonsson Comprehensive Cancer Center and Dept. of Surgery and Dept. of Medicine-Division of Surgical Oncology
Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division and David Geffen School of Medicine and Dept. of Biological Chemistry
Univ. of California, Los Angeles, CA (United States). The Pasarow Mass Spectrometry Lab., Neuropsychiatric Institute-Semel Inst. for Neuroscience and Human Behavior
Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division and The Pasarow Mass Spectrometry Lab., Neuropsychiatric Institute-Semel Inst. for Neuroscience and Human Behavior
Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division and David Geffen School of Medicine and Dept. of Surgery
Univ. of California, Los Angeles, CA (United States) Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division

It is known that 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.

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Research Organization:: Univ. of California, Los Angeles, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Cancer Institute (NCI)

Grant/Contract Number:: SC0012353; R01 CA187678; P30 DK063491; R25 CA098010

OSTI ID:: 1425368

Journal Information:: Nature Communications, Vol. 8, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 32 works

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