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Novel NRF2 ‐activated cancer treatments utilizing synthetic lethality
Author(s) -
Baird Liam,
Kensler Thomas W.,
Yamamoto Masayuki
Publication year - 2022
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.2680
Subject(s) - keap1 , synthetic lethality , cancer research , cancer , prodrug , cancer cell , immune system , biology , pharmacology , medicine , gene , immunology , dna repair , genetics , transcription factor
The KEAP1‐NRF2 pathway regulates the main inducible cellular response to oxidative and electrophilic stresses. Activating mutations in the KEAP1‐NRF2 pathway occur commonly in human cancer, where they contribute to the formation of aggressive tumours that are associated with a poor prognosis for patients. An important clinical feature of these tumours is their defiance to all current anti‐cancer treatment regimens, highlighting the need for the development of new therapeutic strategies to target NRF2‐activated cancers. In this review, we discuss the mechanisms through which acquired NRF2 hyperactivation can result in resistance of tumours to immune checkpoint inhibitor therapies in addition to classical chemotherapeutics, and propose with examples that using a synthetic lethal strategy mediated by NRF2‐target gene‐dependent bioactivation of prodrugs represents a promising strategy to specifically enhance toxicity to heretofore untreatable NRF2‐hyperactivated human tumours.