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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Squamous cell lung cancers (LUSCs) have a complex mutational landscape but lack effective targeted therapies.
• Mutations in NRF2 (NFE2L2) and KEAP1 are common in non-small cell lung cancers (NSCLCs) and affect redox balance.

Purpose of the Study:

• To evaluate the efficacy of TAK-228, a TORC1/2 inhibitor, in NSCLC models and patients with NRF2-activating alterations.
• To investigate TAK-228 as a targeted therapy for advanced NSCLC, particularly LUSC.

Main Methods:

• A Phase 2 clinical trial was conducted in patients with advanced NSCLC harboring NRF2-activating alterations.
• The trial included cohorts of NFE2L2-mutated LUSC, KEAP1-mutated LUSC, and KRAS/NFE2L2- or KEAP1-mutated NSCLC.
• The activity of TAK-228 was assessed, along with potential combination therapy with CB-839 (glutaminase inhibitor).

Main Results:

• TAK-228 demonstrated the most significant efficacy in a LUSC cohort with NFE2L2 alterations.
• The overall response rate was 25%, with a median progression-free survival of 8.9 months in this cohort.
• Concurrent inhibition of glutaminase may overcome metabolic resistance to therapy.

Conclusions:

• TAK-228 exhibits single-agent activity in patients with NRF2-activated LUSC.
• This study highlights the relevance of oncogenic alterations through their metabolic effects.
• This represents a novel metabolic targeting strategy for NSCLC, offering a promising therapy for LUSC patients.