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Sequential redox vulnerabilities with therapeutic potential during the acquisition of drug resistance in BRAFV600E lung adenocarcinoma

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271247 | GEO | 2024/07/02

REPOSITORIES: GEO

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