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| Status |
Public on May 23, 2024 |
| Title |
Enhancing transcription replication conflict targets ecDNA positive cancers [KAS-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. EcDNA renders tumours treatment-resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival. At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA (ssDNA), leading to excessive transcription replication conflicts and replication stress (RS) compared to chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and RS is significantly higher in ecDNA-containing tumours regardless of cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds ssDNA, shows elevated localization on ecDNA in a transcription dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, CHK1. Genetic or pharmacological CHK1 inhibition abrogates the DNA replication check point, causing extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent, and bioavailable oral CHK1 inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric cancer model containing FGFR2 on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer.
This work was delivered as part of the eDyNAmiC team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (CGCATF-2021/100012 and CGCATF-2021/100025) and the National Cancer Institute (OT2CA278688 and OT2CA278635) to H.Y.C., P.S.M., and V.B. This project was supported by NIH RM1-HG007735 (H.Y.C., W.J.G., C.C.).
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| Overall design |
Kethoxal-assisted single-stranded DNA sequencing (KAS-seq) in isogenic cell pair of COLO320 DM and COLO320 HSR, and under transcription inhibition by triptolide, 2 biological replicates each
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| Contributor(s) |
Wang G, Marinov GK, Chang H, Greenleaf WJ |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Dec 07, 2023 |
| Last update date |
May 23, 2024 |
| Contact name |
Guiping Wang |
| E-mail(s) |
gpw@stanford.edu
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| Organization name |
Stanford University
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| Street address |
256 Campus Dr
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| City |
Stanford |
| ZIP/Postal code |
94305 |
| Country |
USA |
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| Platforms (1) |
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| Samples (16)
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| GSM7956915 |
COLO320, DM, DMSO, KAS, rep1 |
| GSM7956916 |
COLO320, DM, DMSO, KAS, rep2 |
| GSM7956917 |
COLO320, HSR, DMSO, KAS, rep1 |
| GSM7956918 |
COLO320, HSR, DMSO, KAS, rep2 |
| GSM7956919 |
COLO320, DM, TPL, KAS, rep1 |
| GSM7956920 |
COLO320, DM, TPL, KAS, rep2 |
| GSM7956921 |
COLO320, HSR, TPL, KAS, rep1 |
| GSM7956922 |
COLO320, HSR, TPL, KAS, rep2 |
| GSM7956923 |
COLO320, DM, DMSO, input, rep1 |
| GSM7956924 |
COLO320, DM, DMSO, input, rep2 |
| GSM7956925 |
COLO320, HSR, DMSO, input, rep1 |
| GSM7956926 |
COLO320, HSR, DMSO, input, rep2 |
| GSM7956927 |
COLO320, DM, TPL, input, rep1 |
| GSM7956928 |
COLO320, DM, TPL, input, rep2 |
| GSM7956929 |
COLO320, HSR, TPL, input, rep1 |
| GSM7956930 |
COLO320, HSR, TPL, input, rep2 |
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| This SubSeries is part of SuperSeries: |
| GSE249657 |
Enhancing transcription replication conflict targets ecDNA positive cancers |
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| Relations |
| BioProject |
PRJNA1049896 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE249655_DM_ecDNA_peaks.broadPeak.gz |
1.4 Kb |
(ftp)(http) |
BROADPEAK |
| GSE249655_HSR_ecDNA_peaks.broadPeak.gz |
575 b |
(ftp)(http) |
BROADPEAK |
| GSE249655_L2614-HSR_DMSO2_normalized_log2Ratio.bw |
148.2 Mb |
(ftp)(http) |
BW |
| GSE249655_L2615-HSR_DMSO3_normalized_log2Ratio.bw |
175.7 Mb |
(ftp)(http) |
BW |
| GSE249655_L2616-HSR_TPL2._normalized_log2Ratio.bw |
189.2 Mb |
(ftp)(http) |
BW |
| GSE249655_L2617-HSR_TPL3._normalized_log2Ratio.bw |
233.1 Mb |
(ftp)(http) |
BW |
| GSE249655_L2618-DM_DMSO2._normalized_log2Ratio.bw |
188.2 Mb |
(ftp)(http) |
BW |
| GSE249655_L2619-DM_DMSO3._normalized_log2Ratio.bw |
203.5 Mb |
(ftp)(http) |
BW |
| GSE249655_L2620-DM_TPL2.2_normalized_log2Ratio.bw |
256.2 Mb |
(ftp)(http) |
BW |
| GSE249655_L2621-DM_TPL3.2_normalized_log2Ratio.bw |
227.3 Mb |
(ftp)(http) |
BW |
SRA Run Selector |
| Raw data are available in SRA |
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