Synapse - Targeting NFE2L2/KEAP1 mutations in advanced NSCLC with the TORC1/2 inhibitor TAK-228

Targeting NFE2L2/KEAP1 mutations in advanced NSCLC with the TORC1/2 inhibitor TAK-228 Journal Article

Authors:	Paik, P. K.; Fan, P. D.; Qeriqi, B.; Namakydoust, A.; Daly, B.; Ahn, L.; Kim, R.; Plodkowski, A.; Ni, A.; Chang, J.; Fanaroff, R.; Ladanyi, M.; de Stanchina, E.; Rudin, C. M.
Article Title:	Targeting NFE2L2/KEAP1 mutations in advanced NSCLC with the TORC1/2 inhibitor TAK-228
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. © 2022 International Association for the Study of Lung Cancer
Keywords:	genetics; mutation; metabolism; carcinoma, non-small-cell lung; lung neoplasms; lung tumor; non small cell lung cancer; transcription factor nrf2; kelch like ech associated protein 1; humans; human; nfe2l2 protein, human; nf-e2-related factor 2; nfe2l2; keap1; sapanisertib; glutaminase; kelch-like ech-associated protein 1; keap1 protein, human; cb-839; squamous cell lung cancer; tak-228
Journal Title:	Journal of Thoracic Oncology
Volume:	18
Issue:	4
ISSN:	1556-0864
Publisher:	Elsevier Inc.
Date Published:	2023-04-01
Start Page:	516
End Page:	526
Language:	English
DOI:	10.1016/j.jtho.2022.09.225
PUBMED:	36240971
PROVIDER:	scopus
PMCID:	PMC10500888
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85141272117&doi=10.1016%2fj.jtho.2022.09.225&partnerID=40&md5=dcf784041d777f2029c0d40d8f6812f7
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF and PubMed -- Corresponding author is MSK author: Paul K. Paik -- Source: Scopus