Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication.

Autor:	Murai J; Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.; Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.; Department of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Japan.; Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan., Ceribelli M; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, Maryland., Fu H; Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Redon CE; Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Jo U; Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Murai Y; Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Aladjem MI; Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Thomas CJ; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, Maryland., Pommier Y; Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2023 Aug 01; Vol. 22 (8), pp. 985-995.
DOI:	10.1158/1535-7163.MCT-22-0552
Abstrakt:	Schlafen 11 (SLFN11) is an increasingly prominent predictive biomarker and a molecular sensor for a wide range of clinical drugs: topoisomerases, PARP and replication inhibitors, and platinum derivatives. To expand the spectrum of drugs and pathways targeting SLFN11, we ran a high-throughput screen with 1,978 mechanistically annotated, oncology-focused compounds in two isogenic pairs of SLFN11-proficient and -deficient cells (CCRF-CEM and K562). We identified 29 hit compounds that selectively kill SLFN11-proficient cells, including not only previously known DNA-targeting agents, but also the neddylation inhibitor pevonedistat (MLN-4924) and the DNA polymerase α inhibitor AHPN/CD437, which both induced SLFN11 chromatin recruitment. By inactivating cullin-ring E3 ligases, pevonedistat acts as an anticancer agent partly by inducing unscheduled re-replication through supraphysiologic accumulation of CDT1, an essential factor for replication initiation. Unlike the known DNA-targeting agents and AHPN/CD437 that recruit SLFN11 onto chromatin in 4 hours, pevonedistat recruited SLFN11 at late time points (24 hours). While pevonedistat induced unscheduled re-replication in SLFN11-deficient cells after 24 hours, the re-replication was largely blocked in SLFN11-proficient cells. The positive correlation between sensitivity to pevonedistat and SLFN11 expression was also observed in non-isogenic cancer cells in three independent cancer cell databases (NCI-60, CTRP: Cancer Therapeutics Response Portal and GDSC: Genomic of Drug Sensitivity in Cancer). The present study reveals that SLFN11 not only detects stressed replication but also inhibits unscheduled re-replication induced by pevonedistat, thereby enhancing its anticancer efficacy. It also suggests SLFN11 as a potential predictive biomarker for pevonedistat in ongoing and future clinical trials. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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