Cell Reports (Sep 2020)
SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells
- 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
Affiliations
- Kathleen Klotz-Noack
- Charité – 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
- Bertram Klinger
- Charité – 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
- Maria Rivera
- EPO Experimentelle Pharmakologie und Onkologie Berlin-Buch GmbH, Robert-Rössle-Str. 10, 13125 Berlin, Germany
- Natalie Bublitz
- Charité – 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
- Florian Uhlitz
- Charité – 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
- Pamela Riemer
- Charité – 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
- Mareen Lüthen
- Charité – 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
- Thomas Sell
- Charité – 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
- Katharina Kasack
- Charité – 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
- Bastian Gastl
- Charité – 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
- Sylvia S.S. Ispasanie
- Charité – 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
- Tincy Simon
- Charité – 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
- Nicole Janssen
- Dr. Margarete Fischer-Bosch – Institute of Clinical Pharmacology, Auerbachstraße 112, 70376 Stuttgart, Germany; University of Tuebingen, 72074 Tuebingen, Germany
- Matthias Schwab
- Dr. 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, Germany
- Johannes Zuber
- Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), 1030 Vienna, Austria; Medical University of Vienna, VBC, 1030 Vienna, Austria
- David Horst
- Charité – 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
- Nils Blüthgen
- Charité – 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, Germany
- Reinhold Schäfer
- Charité – 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, Germany
- Markus Morkel
- Charité – 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
- Christine Sers
- Charité – 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 author
- Journal volume & issue
-
Vol. 32,
no. 12
p. 108184
Abstract
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.
