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Published on: October 8, 2015
SFPQ Depletion Is Synthetically Lethal with BRAFV600E in Colorectal Cancer Cells
Kathleen Klotz-Noack1, Bertram Klinger2, Maria Rivera3
1Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract:
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.
Insights
Targeting BRAF V600E mutations is challenging. Researchers found that depleting the nuclear protein SFPQ causes synthetic lethality in BRAF-mutant cancer cells, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Oncoproteins like BRAF V600E drive cancer but also create vulnerabilities.
- Targeting cytoplasmic signaling in BRAF V600E cancers has led to relapse due to pathway reactivation.
Purpose of the Study:
- To identify novel vulnerabilities in BRAF V600E-driven cancers.
- To explore the synthetic lethal interaction between BRAF V600E and nuclear protein SFPQ.
Main Methods:
- Conducted a loss-of-function shRNA screen to identify genes synthetically lethal with BRAF V600E.
- Depleted SFPQ in BRAF V600E-mutant colorectal and melanoma cell lines.
- Investigated the mechanistic consequences of SFPQ loss on cell proliferation, cell cycle, and DNA replication.
Main Results:
- SFPQ depletion was synthetically lethal with BRAF V600E, decreasing proliferation and inducing S-phase arrest and apoptosis.
- SFPQ loss activated the Chk1-dependent replication checkpoint in BRAF-mutant cells.
- Reduced replication factories and increased replication-transcription collisions were observed upon SFPQ depletion.
Conclusions:
- SFPQ is a vulnerability in BRAF V600E-mutant cancers.
- BRAF V600E-mutant cells are sensitive to combined Chk1 inhibition and replication stress.
- Exploiting nuclear vulnerabilities presents a promising therapeutic avenue for BRAF V600E-driven cancers.
