SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells

Cell Rep. 2020 Sep 22;32(12):108184. doi: 10.1016/j.celrep.2020.108184.


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.

Keywords: Chk1; DNA damage; MAPK signaling; R loops; cell death; organoids; replication stress; synthetic lethality; xenograft.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • PTB-Associated Splicing Factor / metabolism*
  • Proto-Oncogene Proteins B-raf / genetics*
  • 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


  • PTB-Associated Splicing Factor
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Proto-Oncogene Proteins B-raf
  • Rad51 Recombinase
  • Hydroxyurea