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Targeting NRF2 addiction in cancer: synthetic lethal strategies beyond direct inhibition

Melat T Gebru1, David Stokoe1

  • 1Calico Life Sciences LLC, San Francisco, CA, United States.

Frontiers in Cell and Developmental Biology
|June 8, 2026
PubMed

Insights

Constitutive activation of Nuclear factor erythroid 2-related factor 2 (NRF2) promotes cancer therapy resistance. Targeting NRF2-driven metabolic vulnerabilities offers a promising synthetic lethal strategy for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cellular defense pathways.
  • Constitutive NRF2 activation, common in various cancers, promotes tumor growth, drug resistance, and immune evasion.
  • Direct NRF2 inhibition has faced challenges due to its complex biology and 'undruggable' nature.

Purpose of the Study:

  • To review strategies targeting NRF2-driven metabolic dependencies as synthetic lethal vulnerabilities in cancer.
  • To highlight emerging therapeutic approaches, including allosteric KEAP1 activators.
  • To discuss challenges in translating these findings into clinical practice.

Main Methods:

  • Review of current literature on NRF2 function in cancer.
  • Analysis of NRF2-mediated metabolic reprogramming and its role in therapy resistance.
  • Exploration of synthetic lethal strategies targeting metabolic pathways crucial for NRF2-activated tumors.

Main Results:

  • NRF2 activation drives metabolic reprogramming, including glutaminolysis, redox imbalance, and altered nucleotide biosynthesis.
  • Targeting these metabolic dependencies, such as cystine metabolism and ER proteostasis, presents synthetic lethal vulnerabilities.
  • Allosteric activators of KEAP1 are emerging as a potential therapeutic strategy.

Conclusions:

  • Targeting NRF2-driven metabolic vulnerabilities offers a novel therapeutic avenue for resistant cancers.
  • Developing effective therapies requires overcoming challenges related to NRF2's context-dependent biology and systemic toxicity.
  • Further research into allosteric KEAP1 activators and synthetic lethality holds promise for future cancer treatments.
Keywords:
KEAP1Nrf2drug resistanceferroptosisglutaminolysislung cancermetabolic reprogrammingreductive stress

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