Endogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo .

Autor:	Oo ZY; Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia.; The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland. Australia., Stevenson AJ; Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia., Proctor M; Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia., Daignault SM; The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland. Australia., Walpole S; The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland. Australia., Lanagan C; Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia., Chen J; The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland. Australia., Škalamera D; Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia., Spoerri L; The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland. Australia., Ainger SA; The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland. Australia., Sturm RA; The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland. Australia., Haass NK; The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland. Australia., Gabrielli B; Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia. brianG@uq.edu.au.; The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland. Australia.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2018 Jun 15; Vol. 24 (12), pp. 2901-2912. Date of Electronic Publication: 2018 Mar 13.
DOI:	10.1158/1078-0432.CCR-17-2701
Abstrakt:	Purpose: Checkpoint kinase 1 inhibitors (CHEK1i) have single-agent activity in vitro and in vivo Here, we have investigated the molecular basis of this activity. Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines. Results: A subset of melanoma cell lines is hypersensitive to CHEK1i-induced cell death in vitro , and the drug effectively inhibits tumor growth in vivo In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyperphosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S-phase cell-cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumors appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i. Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated with increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumors, and may be a useful marker of replication stress in vivo Clin Cancer Res; 24(12); 2901-12. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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