In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAFV600E lung adenocarcinoma

• Published in: Cell reports. Medicine Vol. 5; no. 8
• Main Authors: Nokin, Marie-Julie, Darbo, Elodie, Richard, Elodie, San José, Sonia, de Hita, Sergio, Prouzet-Mauleon, Valérie, Turcq, Béatrice, Gerardelli, Laura, Crake, Rebekah, Velasco, Valérie, Koopmansch, Benjamin, Lambert, Frederic, Xue, Jenny Y, Sang, Ben, Horne, Julie, Ziemons, Eric, Villanueva, Alberto, Blomme, Arnaud, Herfs, Michael, Cataldo, Didier, Calvayrac, Olivier, Porporato, Paolo, Nadal, Ernest, Lito, Piro, Jänne, Pasi A, Ricciuti, Biagio, Awad, Mark M, Ambrogio, Chiara, Santamaría, David
• Format: Journal Article
• Language: English
• Published: Cell Press 01-08-2024
• Subjects: Life Sciences
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101663

The current targeted therapy for BRAFV600E-mutant lung cancer consists of a dual blockade of RAF/MEK kinases often combining dabrafenib/trametinib (D/T). This regimen extends survival when compared to single-agent treatments, but disease progression is unavoidable. By using whole-genome CRISPR screening and RNA sequencing, we characterize the vulnerabilities of both persister and D/T-resistant cellular models. Oxidative stress together with concomitant induction of antioxidant responses is boosted by D/T treatment. However, the nature of the oxidative damage, the choice of redox detoxification systems, and the resulting therapeutic vulnerabilities display stage-specific differences. Persister cells suffer from lipid peroxidation and are sensitive to ferroptosis upon GPX4 inhibition in vivo. Biomarkers of lipid peroxidation are detected in clinical samples following D/T treatment. Acquired alterations leading to mitogen-activated protein kinase (MAPK) reactivation enhance cystine transport to boost GPX4-independent antioxidant responses. Similarly to BRAFV600E-mutant melanoma, histone deacetylase (HDAC) inhibitors decrease D/T-resistant cell viability and extend therapeutic response in vivo.