SFPQ Depletion Is Synthetically Lethal with BRAF V600E in Colorectal Cancer Cells

• Published in: Cell reports (Cambridge) Vol. 32; no. 12; p. 108184
• Main Authors: Klotz-Noack, Kathleen, Klinger, Bertram, Rivera, Maria, Bublitz, Natalie, Uhlitz, Florian, Riemer, Pamela, Lüthen, Mareen, Sell, Thomas, Kasack, Katharina, Gastl, Bastian, Ispasanie, Sylvia S S, Simon, Tincy, Janssen, Nicole, Schwab, Matthias, Zuber, Johannes, Horst, David, Blüthgen, Nils, Schäfer, Reinhold, Morkel, Markus, Sers, Christine
• Format: Journal Article
• Language: English
• Published: United States 22.09.2020
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; Checkpoint Kinase 1 - metabolism; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA Damage; DNA Repair - drug effects; DNA Repair - genetics; DNA Replication - drug effects; DNA Replication - genetics; Female; Humans; Hydroxyurea - pharmacology; Mice, Nude; Mutation - genetics; Proto-Oncogene Proteins B-raf - genetics; PTB-Associated Splicing Factor - metabolism; Rad51 Recombinase - metabolism; Reproducibility of Results; S Phase - drug effects; S Phase - genetics; Stress, Physiological - drug effects; Synthetic Lethal Mutations - genetics; Tumor Suppressor p53-Binding Protein 1 - metabolism; R loops; replication stress; cell death; xenograft; DNA damage; organoids; synthetic lethality; Chk1; MAPK signaling
• ISSN: 2211-1247

Oncoproteins such as the BRAF kinase endow cancer cells with malignant properties, but they also create unique vulnerabilities. Targeting of BRAF -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 BRAF in a loss-of-function shRNA screen. SFPQ depletion decreases proliferation and specifically induces S-phase arrest and apoptosis in BRAF -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 BRAF -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 BRAF .