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Targeting NFE2L2/KEAP1 Mutations in Advanced NSCLC With the TORC1/2 Inhibitor TAK-228. | LitMetric

Targeting NFE2L2/KEAP1 Mutations in Advanced NSCLC With the TORC1/2 Inhibitor TAK-228.

J Thorac Oncol

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York.

Published: April 2023

AI Article Synopsis

  • This study highlights the ongoing challenges in treating squamous cell lung cancers (LUSCs) despite advances in understanding their genetic mutations, particularly focusing on NRF2 and KEAP1 mutations that affect redox balance.* -
  • The research demonstrates the effectiveness of TAK-228, a TORC1/2 inhibitor, in patients with advanced NSCLC featuring NRF2-activating mutations, showing a 25% response rate and 8.9 months of median progression-free survival.* -
  • The findings suggest that combining TAK-228 with glutaminase inhibitors may help overcome treatment resistance, marking a significant step toward targeted therapies for LUSC patients.*

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10500888PMC
http://dx.doi.org/10.1016/j.jtho.2022.09.225DOI Listing

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