医学
克拉斯
肿瘤科
KEAP1型
癌症研究
内科学
靶向治疗
谷氨酰胺酶
癌症
受体
结直肠癌
转录因子
基因
生物
遗传学
谷氨酸受体
作者
Paul K. Paik,Pang-Dian Fan,Besnik Qeriqi,Azadeh Namakydoust,Bobby Daly,Linda S. Ahn,Rachel Kim,Andrew J. Plodkowski,Ai Ni,Jason C. Chang,Rachel Fanaroff,Marc Ladanyi,Elisa de Stanchina,Charles M. Rudin
标识
DOI:10.1016/j.jtho.2022.09.225
摘要
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.
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