SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells.

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. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

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. 2020 Sep 22;32(12):108184

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PMID: 32966782

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