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; p. 101663
• 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 Web Resource
• Language: English
• Published: Elsevier Inc 01-08-2024; Cell Press; Elsevier
• Subjects: Adenocarcinoma of Lung; Animals; BRAF oncogene; Cell Line, Tumor; Drug Resistance, Neoplasm; Ferroptosis; GPX4 inhibition; HDAC inhibition; Histone Deacetylase Inhibitors; Human health sciences; Humans; Imidazoles; Life Sciences; Lipid Peroxidation; lung adenocarcinoma; Lung Neoplasms; Mice; Mutation; Oncologie; Oncology; Oxidative Stress; Oximes; persister cells; Phospholipid Hydroperoxide Glutathione Peroxidase; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sciences de la santé humaine; targeted therapy; Xenograft Model Antitumor Assays; targeted therapy; HDAC inhibition; ferroptosis; BRAF oncogene; GPX4 inhibition; lung adenocarcinoma; persister cells
• 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.
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•Unbiased genetic screen identifies ferroptosis as DTP vulnerability in BRAFV600E LUAD•GPX4 inhibitors extend survival when applied at early disease relapse•Relapsed tumors display biomarkers indicative of sensitivity to ferroptosis triggers•Acquired mutations restoring MAPK signaling sensitize tumors to HDAC inhibition
Nokin et al. identify two redox-related cellular states that involve an adaptive drug-tolerant stage followed by a genetic-defined resistance phase in BRAFV600E-driven lung cancer. Timely treatments with small molecules (GPX4 and HDAC inhibitors) that further enhance the resulting oxidative stress delay disease progression in vivo.