A checkpoint kinase 1 inhibitor sensitises cancer cells to dihydroorotate dehydrogenase inhibition

The present invention relates to the field of cancer treatment. In this study, the inventors sought to investigate whether this antiproliferative effect of DHODH inhibitors could be enhanced by combining Chk1 kinase inhibition. They show that the effect of the DHODH inhibitor teriflunomide was amplified when cells were subsequently exposed to PF477736 Chk1 inhibitor. Flow cytometry analyses revealed substantial accumulations of cells in S and G2/M phases, followed by increased cytotoxicity which was characterised by caspase 3-dependent induction of cell death. Associating PF477736 with teriflunomide significantly sensitised SUM159 and HCC1937 human triple negative breast cancer cell line to dihydroorotate dehydrogenase inhibition. More, the combination of the DHODH inhibitor with the Chk1 inhibitor in a significant lower dose allow to minimize the off-target effects of the Chk1 inhibitor. Altogether these results suggest that combining DHODH and Chk1 inhibitions may be a strategy worth considering as a potential alternative to conventional chemotherapies. Thus, the present invention relates to an inhibitor of DHODH and an inhibitor of Chk1 for use in the treatment of a cancer in a subject in need thereof.

Keywords: combination, DHODH, Chk1 inhibitor
Patent Application number: EP17305941.1
Inventors:
Stephanie ARNOULDGenevieve RODIERClaude SARDET
Publications:
Oncotarget. 2017 Jul 12;8(56):95206-95222. doi: 10.18632/oncotarget.19199. eCollection 2017 Nov 10.

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