BRCAness, SLFN11 and RB1 loss predict response to topoisomerase I inhibitors in triple negative breast cancers
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ABSTRACT:
PROVIDER: PRJNA597843 | ENA |
REPOSITORIES: ENA
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Project description:Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.
| S-EPMC8662740 | biostudies-literature
Project description:Expression data from patient-derived xenografts of human triple-negative breast cancers
2019-12-28 | GSE142639 | GEO
Project description:Schlafen family member 11 (SLFN11) increases sensitivity to replicative stress and has been proposed as a biomarker to predict sensitivity to DNA damaging agents (DDA). However, the role of SLFN11 in pediatric cancer has not been well explored. In this study, we found that protein expression strongly correlated with response to the PARP inhibitor talazoparib and the topoisomerase I inhibitor irinotecan in sarcoma cell lines, with SLFN11 knockout resulting in significant loss of sensitivity in vitro and in vivo. However, in contrast to its activity in adult tumors, high SLFN11 expression did not correlate with favorable outcome in a retrospective study of children with sarcoma. Our work suggests that the potential of SLFN11 to act as a biomarker may be limited to certain tumor backgrounds or contexts, and that impaired apoptotic response may be one targetable mechanism of resistance to DDA-induced replicative stress
2022-04-08 | GSE181094 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140175 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140932 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140936 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140935 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140934 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140933 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140937 | GEO