Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors.

Abstract:

:p53-mutated tumors often exhibit increased resistance to standard chemotherapy and enhanced metastatic potential. Here we demonstrate that inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme of the de novo pyrimidine synthesis pathway, effectively decreases proliferation of cancer cells via induction of replication and ribosomal stress in a p53- and checkpoint kinase 1 (Chk1)-dependent manner. Mechanistically, a block in replication and ribosomal biogenesis result in p53 activation paralleled by accumulation of replication forks that activate the ataxia telangiectasia and Rad3-related kinase/Chk1 pathway, both of which lead to cell cycle arrest. Since in the absence of functional p53 the cell cycle arrest fully depends on Chk1, combined DHODH/Chk1 inhibition in p53-dysfunctional cancer cells induces aberrant cell cycle re-entry and erroneous mitosis, resulting in massive cell death. Combined DHODH/Chk1 inhibition effectively suppresses p53-mutated tumors and their metastasis, and therefore presents a promising therapeutic strategy for p53-mutated cancers.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Hubackova S,Davidova E,Boukalova S,Kovarova J,Bajzikova M,Coelho A,Terp MG,Ditzel HJ,Rohlena J,Neuzil J

doi

10.1038/s41419-020-2224-7

subject

Has Abstract

pub_date

2020-02-07 00:00:00

pages

110

issue

2

issn

2041-4889

pii

10.1038/s41419-020-2224-7

journal_volume

11

pub_type

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