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The KEAP1-NRF2 System as a Molecular Target of Cancer Treatment

Keiko Taguchi1,2,3, Masayuki Yamamoto1,2,3

  • 1Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan.

Cancers
|December 30, 2020
PubMed

Insights

The KEAP1-NRF2 pathway plays a dual role in cancer, acting as both an oncogene and tumor suppressor. Targeting this system with NRF2 inhibitors or inducers offers potential cancer therapeutics.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The Kelch-like ECH-associated protein (KEAP1)-Nuclear factor erythroid-derived 2-like 2 (NRF2) system is crucial in cancer research due to NRF2's context-dependent oncogenic or tumor-suppressive roles.
  • NRF2-addicted cancers display high NRF2 expression, often due to mutations in KEAP1 or NRF2 genes, leading to NRF2 stabilization and accumulation.

Purpose of the Study:

  • To explore the multifaceted roles of the KEAP1-NRF2 system in cancer development and suppression.
  • To investigate the therapeutic potential of modulating the KEAP1-NRF2 pathway in cancer treatment.

Main Methods:

  • Analysis of somatic mutations in KEAP1 and NRF2 genes in NRF2-addicted cancers.
  • Investigation of NRF2's role in cytoprotection, including antioxidative, anti-electrophilic, and metabolic reprogramming pathways.
  • Evaluation of the impact of NRF2 activation in immune cells on cancer cell growth.

Main Results:

  • Mutations in KEAP1 or NRF2 stabilize NRF2, conferring a survival advantage to cancer cells in harsh microenvironments.
  • NRF2-addicted cancers exploit NRF2's cytoprotective functions for survival and proliferation.
  • NRF2 activation in immune cells demonstrates significant cancer growth suppression.

Conclusions:

  • The KEAP1-NRF2 system is integral to both cancer promotion and inhibition.
  • Both NRF2 inhibitors and inducers represent promising therapeutic strategies for cancers characterized by high NRF2 activity.
Keywords:
KEAP1NRF2NRF2-addicted cancersadaptive response

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