Sequential redox vulnerabilities with therapeutic potential during the acquisition of drug resistance in BRAFV600E lung adenocarcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1130517 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29672770.fastq.gz | Fastqsanger.gz | |||
| SRR29672771.fastq.gz | Fastqsanger.gz | |||
| SRR29672772.fastq.gz | Fastqsanger.gz |
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Project description:The current targeted therapy for lung cancer patients harbouring BRAFV600E alterations consists of a dual blockade of RAF and MEK kinases often combining dabrafenib with trametinib (D/T). This regimen results in extended survival when compared to single agent treatments but, as with other targeted therapies, disease progression is unavoidable. There is limited information of how BRAFV600E-driven lung adenocarcinomas adapt to this targeted treatment and persist before clinical relapse is detected. At this point, a significant fraction of these resistant tumours display mutations in other members of the RAS-ERK pathway and counteract the inhibitors effect by reactivating oncogenic signalling. We demonstrate here that oxidative stress together with the concomitant induction of antioxidant responses is a prominent and early feature boosted by D/T treatment. However, the nature of the oxidative damage and the choice of redox detoxification systems elicited by cancer cells display substantial differences during the process leading to the onset of drug resistance. While persister cells suffer from lipid peroxidation and strongly rely on GPX4 to prevent ferroptosis-driven cell death, D/T resistant tumours harbouring NRAS secondary mutations enhance cystine transport to boost antioxidant responses. Accordingly, timely inhibition of these detox programs by GPX4 or HDAC inhibitors decrease resistant cell viability and extend therapeutic efficacy.
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Project description: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.
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Project description: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.
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