PLX003120

GSE116631: Loss of SFPQ is synthetically lethal with BRAFV600E in colorectal cancer cells

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Oncogenes such as BRAFV600E kinase entrust cancer cells with novel properties that increase their fitness, but they also create unique vulnerabilies. To date, targeting of the cytoplasmic kinase network to exploit BRAFV600E-induced susceptibilities has proven largely ineffective in the clinic, since patients relapse with reactivation of the silenced signaling pathways, resulting in secondary resistance. To identify weaknesses of BRAFV600E-driven cancer cells downstream of the kinase signaling network, we performed a loss-of-function shRNA screen targeting nuclear targets of BRAFV600E in an inducible isogenic colon cancer cell line system. We identified the multifunctional protein SFPQ to be synthetically lethal with BRAFV600E. BRAFV600E-driven colon cancer and melanoma cells showed decreased proliferation and increased apoptosis in cell culture and reduced growth in xenograft after loss of SFPQ. Mechanistically, SFPQ depletion triggered the Chk1-dependent replication checkpoint specifically in cells with oncogenic BRAF. We found that in these cells replication stress occurred in the absence of increased levels of reactive oxygen species or DNA damage. Instead, cells stalled in S-Phase with hallmark signs of impaired maintenance of 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 that exploit nuclear vulnerabilites induced by BRAFV600E. SOURCE: Florian Uhlitz Charité - Universitätsmedizin Berlin