論文 - 詳細
| RRC ID | 78706 |
|---|---|
| 著者 | Paik PK, Fan PD, Qeriqi B, Namakydoust A, Daly B, Ahn L, Kim R, Plodkowski A, Ni A, Chang J, Fanaroff R, Ladanyi M, de Stanchina E, Rudin CM. |
| タイトル | Targeting NFE2L2/KEAP1 Mutations in Advanced NSCLC With the TORC1/2 Inhibitor TAK-228. |
| ジャーナル | J Thorac Oncol |
| Abstract |
INTRODUCTION:Increased insight into the mutational landscape of squamous cell lung cancers (LUSCs) in the past decade has not translated into effective targeted therapies for patients with this disease. NRF2, encoded by NFE2L2, and its upstream regulator, KEAP1, control key aspects of redox balance and are frequently mutated in NSCLCs. METHODS:Here, we describe the specific potent activity of TAK-228, a TORC1/2 inhibitor, in NSCLC models harboring NRF2-activating alterations and results of a phase 2 clinical trial of TAK-228 in patients with advanced NSCLC harboring NRF2-activating alterations including three cohorts (NFE2L2-mutated LUSC, KEAP1-mutated LUSC, KRAS/NFE2L2- or KEAP1-mutated NSCLC). RESULTS:TAK-228 was most efficacious in a LUSC cohort with NFE2L2 alterations; the overall response rate was 25% and median progression-free survival was 8.9 months. Additional data suggest that concurrent inhibition of glutaminase with the glutaminase inhibitor CB-839 might overcome metabolic resistance to therapy in these patients. CONCLUSIONS:TAK-228 has single-agent activity in patients with NRF2-activated LUSC. This study reframes oncogenic alterations as biologically relevant based on their downstream effects on metabolism. This trial represents, to the best of our knowledge, the first successful attempt at metabolically targeting NSCLC and identifies a promising targeted therapy for patients with LUSC, who are bereft of genotype-directed therapies. |
| 巻・号 | 18(4) |
| ページ | 516-526 |
| 公開日 | 2023-4-1 |
| DOI | 10.1016/j.jtho.2022.09.225 |
| PII | S1556-0864(22)01825-1 |
| PMID | 36240971 |
| PMC | PMC10500888 |
| MeSH | Carcinoma, Non-Small-Cell Lung* / drug therapy Carcinoma, Non-Small-Cell Lung* / genetics Carcinoma, Non-Small-Cell Lung* / metabolism Glutaminase / genetics Glutaminase / metabolism Glutaminase / therapeutic use Humans Kelch-Like ECH-Associated Protein 1 / genetics Kelch-Like ECH-Associated Protein 1 / metabolism Lung Neoplasms* / drug therapy Lung Neoplasms* / genetics Lung Neoplasms* / metabolism Mutation NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism |
| リソース情報 | |
| ヒト・動物細胞 | LK-2(RCB1970) |