Novel NRF2-activated cancer treatments utilizing synthetic lethality

被引：16

作者：

Baird, Liam ^{[1
,2
]}

Kensler, Thomas W. ^{[3
]}

Yamamoto, Masayuki ^{[1
,2
,4
]}

机构：

[1] Tohoku Univ, Dept Med Biochem, Grad Sch Med, Sendai, Miyagi, Japan

[2] Tohoku Univ, Adv Res Ctr Innovat Next Generat Med INGEM, Sendai, Miyagi, Japan

[3] Fred Hutchinson Canc Res Ctr, Translat Res Program, 1124 Columbia St, Seattle, WA 98104 USA

[4] Tohoku Univ, Tohoku Med Megabank Org, Sendai, Miyagi, Japan

来源：

IUBMB LIFE | 2022年 / 74卷 / 12期

基金：

日本学术振兴会;

关键词：

bioactivation; cancer; KEAP1; mitomycin C; NRF2; oxidative stress; prodrug; stress response; synthetic lethal; CELL LUNG-CANCER; COOCCURRING GENOMIC ALTERATIONS; TRANSCRIPTION FACTOR NRF2; PROTEIN; 90; INHIBITOR; PHASE-II TRIAL; MITOMYCIN-C; OXIDATIVE STRESS; BREAST-CANCER; HYDROCHLORIDE IPI-504; MUTATIONAL LANDSCAPE;

D O I：

10.1002/iub.2680

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1209 / 1231

页数：23

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