SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells

SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells

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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 fp9550bk 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 iphone 13 price ohio 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.