In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAF(V600E) lung adenocarcinoma Journal Article
| Authors: | Nokin, M. J.; Darbo, E.; Richard, E.; San José, S.; de Hita, S.; Prouzet-Mauleon, V.; Turcq, B.; Gerardelli, L.; Crake, R.; Velasco, V.; Koopmansch, B.; Lambert, F.; Xue, J. Y.; Sang, B.; Horne, J.; Ziemons, E.; Villanueva, A.; Blomme, A.; Herfs, M.; Cataldo, D.; Calvayrac, O.; Porporato, P.; Nadal, E.; Lito, P.; Jänne, P. A.; Ricciuti, B.; Awad, M. M.; Ambrogio, C.; Santamaría, D. |
| Article Title: | In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAF(V600E) lung adenocarcinoma |
| Abstract: | 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. © 2024 The Authors |
| Keywords: | mitogen activated protein kinase; controlled study; protein expression; treatment response; unclassified drug; human cell; genetics; mutation; histone deacetylase inhibitor; nonhuman; polymerase chain reaction; mouse; animal; metabolism; animals; mice; animal tissue; cell viability; pharmacodynamics; gene amplification; gene expression; tumor volume; lung neoplasms; animal experiment; animal model; drug effect; drug resistance; drug screening; pathology; drug resistance, neoplasm; xenograft model antitumor assays; enzyme inhibitor; cell line, tumor; pyrimidinone derivative; pyridones; pyrimidinones; lung tumor; lung adenocarcinoma; tumor cell line; western blotting; immunoblotting; vorinostat; histone deacetylase inhibitors; pleura effusion; targeted therapy; oxidative stress; detoxification; tumor growth; drug therapy; clonogenic assay; fluorescence activated cell sorting; atorvastatin; simvastatin; lipid peroxidation; drug tolerance; panobinostat; b raf kinase; disease exacerbation; deferoxamine mesylate; deferoxamine; glutathione; proto-oncogene proteins b-raf; braf protein, human; imidazoles; rna extraction; imidazole derivative; mevinolin; adenocarcinoma of lung; puromycin; vulnerability; dabrafenib; trametinib; mapk signaling; ferroptosis; oximes; humans; human; female; article; whole genome sequencing; rna sequencing; cell growth assay; clustered regularly interspaced short palindromic repeat; mtt assay; gene set enrichment analysis; oxime; braf oncogene; real time reverse transcription polymerase chain reaction; phospholipid hydroperoxide glutathione peroxidase; dipyrone; illumina sequencing; sodium selenite; crispr associated endonuclease cas9; gpx4 inhibition; hdac inhibition; persister cells; phospholipid hydroperoxide glutathione peroxidase inhibitor; drug persistent lung adenocarcinoma; drug resistant lung adenocarcinoma |
| Journal Title: | Cell Reports Medicine |
| Volume: | 5 |
| Issue: | 8 |
| ISSN: | 2666-3791 |
| Publisher: | Cell Press |
| Date Published: | 2024-08-20 |
| Start Page: | 101663 |
| Language: | English |
| DOI: | 10.1016/j.xcrm.2024.101663 |
| PUBMED: | 39094577 |
| PROVIDER: | scopus |
| PMCID: | PMC11384943 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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