Synergistic targeting of CHK1 and mTOR in MYC-driven tumors.

Carcinogenesis
Xiaoxue SongHudan Liu

Abstract

Deregulation of v-myc avian myelocytomatosis viral oncogene homolog (MYC) occurs in a broad range of human cancers and often predicts poor prognosis and resistance to therapy. However, directly targeting oncogenic MYC remains unsuccessful, and indirectly inhibiting MYC emerges as a promising approach. Checkpoint kinase 1 (CHK1) is a protein kinase that coordinates the G2/M cell cycle checkpoint and protects cancer cells from excessive replicative stress. Using c-MYC-mediated T-cell acute lymphoblastic leukemia (T-acute lymphoblastic leukemia) and N-MYC-driven neuroblastoma as model systems, we reveal that both c-MYC and N-MYC directly bind to the CHK1 locus and activate its transcription. CHIR-124, a selective CHK1 inhibitor, impairs cell viability and induces remarkable synergistic lethality with mTOR inhibitor rapamycin in MYC-overexpressing cells. Mechanistically, rapamycin inactivates carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), the essential enzyme for the first three steps of de novo pyrimidine synthesis, and deteriorates CHIR-124-induced replicative stress. We further demonstrate that dual treatments impede T-acute lymphoblastic leukemia and neuroblastoma progression in vivo. T...Continue Reading

References

Jun 2, 1997·The EMBO Journal·W A WeissJ M Bishop
Jun 11, 1999·Genes & Development·A C GingrasN Sonenberg
Sep 17, 1999·Molecular Cell·D W Felsher, J M Bishop
Jun 5, 2002·Genome Research·W James KentDavid Haussler
Feb 8, 2003·Science·David M LangenauA Thomas Look
Aug 16, 2006·Oncogene·Y L ChoiH Mano
Oct 17, 2008·Genes & Development·Martin Eilers, Robert N Eisenman
Dec 3, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Susan L CohnUNKNOWN INRG Task Force
Jun 19, 2010·The New England Journal of Medicine·John M Maris
Feb 4, 2011·Proceedings of the National Academy of Sciences of the United States of America·Kristina A ColeJohn M Maris
Nov 29, 2011·Nature Structural & Molecular Biology·Matilde MurgaOscar Fernandez-Capetillo
Mar 1, 2012·The Journal of Experimental Medicine·Andres J López-ContrerasOscar Fernandez-Capetillo
Apr 3, 2012·Cell·Chi V Dang
Apr 25, 2013·International Journal of Cancer. Journal International Du Cancer·Youwei Zhang, Tony Hunter
Feb 11, 2014·Cell Metabolism·Jing LiJohn Blenis
Apr 25, 2015·Nature Reviews. Cancer·Hélène GaillardAndrés Aguilera
Mar 12, 2017·Cell·Robert A Saxton, David M Sabatini
Oct 22, 2017·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Zhaojun QiuJunran Zhang
Mar 13, 2018·Signal Transduction and Targeted Therapy·Hui ChenGuoliang Qing
Apr 17, 2019·Progress in Biophysics and Molecular Biology·Noa LammAnthony J Cesare
May 10, 2019·Nature·Mahmoud GhandiWilliam R Sellers
Nov 5, 2019·Cancer Cell·Huiying HanSarki A Abdulkadir

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Citations

Jul 3, 2021·International Journal of Molecular Sciences·Laura Curti, Stefano Campaner
Jul 14, 2021·Expert Opinion on Pharmacotherapy·Parmida Sadat PezeshkiNima Rezaei

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