SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells II

Oncoproteins such as the BRAFV600E kinase entrust cancer cells with malignant properties, but they also create unique vulnerabilies. Therapeutic targeting of the BRAFV600E-driven cytoplasmic signaling network has proven ineffective, since patients regularly relapse with reactivation of the targeted signaling pathways. Here, we identified the nuclear protein SFPQ to be synthetically lethal with BRAFV600E in a loss-of-function shRNA screen. SFPQ depletion decreased proliferation and induced apoptosis in BRAFV600E-driven colorectal and melanoma cells, and reduced tumor growth in xenografts. Mechanistically, SFPQ loss in BRAF-mutant cancer cells triggered the Chk1-dependent replication checkpoint, resulting in replication stress in the absence of overt DNA damage. Affected cells stalled in S-Phase with hallmark signs of impaired replication factories. Induction of BRAFV600E and concomitant loss of SFPQ sensitized cells to a combination of DNA replication checkpoint inhibitors and chemically induced replication stress, pointing towards future therapeutic approaches exploiting nuclear vulnerabilities induced by BRAFV600E. Overall design: CaCo2 wt shRen (Control shRNA), CaCo2 wt shSFPQ, CaCo2 BRAFV600E shControl and Caco2 BRAFV600E shSFPQ were treated with doxycycline for 96h to induce an ectopic expression of the shRNAs and if applicable the BRAF oncogene. The RNA was isolated, depleted of ribosomal RNA and paired-end sequenced (125 bp).