SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells
Summary: Oncoproteins such as the BRAFV600E kinase endow cancer cells with malignant properties, but they also create unique vulnerabilities. Targeting of BRAFV600E-driven cytoplasmic signaling networks has proved ineffective, as patients regularly relapse with reactivation of the targeted pathways....
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720311736 |
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doaj-2950671e43df461fba99d304a2fcf743 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Kathleen Klotz-Noack Bertram Klinger Maria Rivera Natalie Bublitz Florian Uhlitz Pamela Riemer Mareen Lüthen Thomas Sell Katharina Kasack Bastian Gastl Sylvia S.S. Ispasanie Tincy Simon Nicole Janssen Matthias Schwab Johannes Zuber David Horst Nils Blüthgen Reinhold Schäfer Markus Morkel Christine Sers |
| spellingShingle |
Kathleen Klotz-Noack Bertram Klinger Maria Rivera Natalie Bublitz Florian Uhlitz Pamela Riemer Mareen Lüthen Thomas Sell Katharina Kasack Bastian Gastl Sylvia S.S. Ispasanie Tincy Simon Nicole Janssen Matthias Schwab Johannes Zuber David Horst Nils Blüthgen Reinhold Schäfer Markus Morkel Christine Sers SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells Cell Reports MAPK signaling Chk1 replication stress R loops cell death synthetic lethality |
| author_facet |
Kathleen Klotz-Noack Bertram Klinger Maria Rivera Natalie Bublitz Florian Uhlitz Pamela Riemer Mareen Lüthen Thomas Sell Katharina Kasack Bastian Gastl Sylvia S.S. Ispasanie Tincy Simon Nicole Janssen Matthias Schwab Johannes Zuber David Horst Nils Blüthgen Reinhold Schäfer Markus Morkel Christine Sers |
| author_sort |
Kathleen Klotz-Noack |
| title |
SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells |
| title_short |
SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells |
| title_full |
SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells |
| title_fullStr |
SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells |
| title_full_unstemmed |
SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells |
| title_sort |
sfpq depletion is synthetically lethal with brafv600e in colorectal cancer cells |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2020-09-01 |
| description |
Summary: Oncoproteins such as the BRAFV600E kinase endow cancer cells with malignant properties, but they also create unique vulnerabilities. Targeting of BRAFV600E-driven cytoplasmic signaling networks has proved ineffective, as patients regularly relapse with reactivation of the targeted pathways. We identify the nuclear protein SFPQ to be synthetically lethal with BRAFV600E in a loss-of-function shRNA screen. SFPQ depletion decreases proliferation and specifically induces S-phase arrest and apoptosis in BRAFV600E-driven colorectal and melanoma cells. Mechanistically, SFPQ loss in BRAF-mutant cancer cells triggers the Chk1-dependent replication checkpoint, results in decreased numbers and reduced activities of replication factories, and increases collision between replication and transcription. We find that BRAFV600E-mutant cancer cells and organoids are sensitive to combinations of Chk1 inhibitors and chemically induced replication stress, pointing toward future therapeutic approaches exploiting nuclear vulnerabilities induced by BRAFV600E. |
| topic |
MAPK signaling Chk1 replication stress R loops cell death synthetic lethality |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124720311736 |
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doaj-2950671e43df461fba99d304a2fcf7432020-11-25T03:26:02ZengElsevierCell Reports2211-12472020-09-013212108184SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer CellsKathleen Klotz-Noack0Bertram Klinger1Maria Rivera2Natalie Bublitz3Florian Uhlitz4Pamela Riemer5Mareen Lüthen6Thomas Sell7Katharina Kasack8Bastian Gastl9Sylvia S.S. Ispasanie10Tincy Simon11Nicole Janssen12Matthias Schwab13Johannes Zuber14David Horst15Nils Blüthgen16Reinhold Schäfer17Markus Morkel18Christine Sers19Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; IRI Life Sciences & Institute of Theoretical Biology, Humboldt-Universität zu Berlin, 10115 Berlin, GermanyEPO Experimentelle Pharmakologie und Onkologie Berlin-Buch GmbH, Robert-Rössle-Str. 10, 13125 Berlin, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; IRI Life Sciences & Institute of Theoretical Biology, Humboldt-Universität zu Berlin, 10115 Berlin, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; IRI Life Sciences & Institute of Theoretical Biology, Humboldt-Universität zu Berlin, 10115 Berlin, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, GermanyDr. Margarete Fischer-Bosch – Institute of Clinical Pharmacology, Auerbachstraße 112, 70376 Stuttgart, Germany; University of Tuebingen, 72074 Tuebingen, GermanyDr. Margarete Fischer-Bosch – Institute of Clinical Pharmacology, Auerbachstraße 112, 70376 Stuttgart, Germany; Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tuebingen, Auf der Morgenstelle 8, 72074 Tuebingen, Germany; German Cancer Consortium (DKTK), Partner Site Tuebingen and German Cancer Research Center (DKFZ), Heidelberg, GermanyResearch Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), 1030 Vienna, Austria; Medical University of Vienna, VBC, 1030 Vienna, AustriaCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; IRI Life Sciences & Institute of Theoretical Biology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany; Charité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Chariteplatz 1, 10117 Berlin, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany; Corresponding authorSummary: Oncoproteins such as the BRAFV600E kinase endow cancer cells with malignant properties, but they also create unique vulnerabilities. Targeting of BRAFV600E-driven cytoplasmic signaling networks has proved ineffective, as patients regularly relapse with reactivation of the targeted pathways. We identify the nuclear protein SFPQ to be synthetically lethal with BRAFV600E in a loss-of-function shRNA screen. SFPQ depletion decreases proliferation and specifically induces S-phase arrest and apoptosis in BRAFV600E-driven colorectal and melanoma cells. Mechanistically, SFPQ loss in BRAF-mutant cancer cells triggers the Chk1-dependent replication checkpoint, results in decreased numbers and reduced activities of replication factories, and increases collision between replication and transcription. We find that BRAFV600E-mutant cancer cells and organoids are sensitive to combinations of Chk1 inhibitors and chemically induced replication stress, pointing toward future therapeutic approaches exploiting nuclear vulnerabilities induced by BRAFV600E.http://www.sciencedirect.com/science/article/pii/S2211124720311736MAPK signalingChk1replication stressR loopscell deathsynthetic lethality |