ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways.
Thuc M LeSoumya PoddarJoseph R CapriEvan R AbtWoosuk KimLiu WeiNhu T UongChloe M ChengDaniel BraasMina NikanjamPeter RixDaria MerkurjevJesse ZaretskyHarley I KornblumAntoni RibasHarvey R HerschmanJulian WhiteleggeKym F FaullTimothy R DonahueJohannes CzerninCaius G RaduPublished in: Nature communications (2017)
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.Leukemic cells depend on the nucleotide synthesis pathway to proliferate. Here the authors use metabolomics and proteomics to show that inhibition of ATR reduced the activity of these pathways thus providing a valuable therapeutic target in leukemia.
Keyphrases
- induced apoptosis
- acute myeloid leukemia
- bone marrow
- dna damage response
- acute lymphoblastic leukemia
- cell cycle arrest
- free survival
- mass spectrometry
- oxidative stress
- endoplasmic reticulum stress
- type diabetes
- tyrosine kinase
- metabolic syndrome
- cell proliferation
- protein kinase
- young adults
- dna repair
- high fat diet induced
- insulin resistance
- drug delivery
- cell wall
- heat stress