A NRF2 inhibitor selectively sensitizes KEAP1 mutant tumor cells to cisplatin and gefitinib by restoring NRF2-inhibitory function of KEAP1 mutants
Tahar Aboulkassim,
Xiaohong Tian,
Qiang Liu,
Dinghong Qiu,
Mark Hancock,
Jian Hui Wu,
Gerald Batist
Affiliations
Tahar Aboulkassim
Segal Cancer Center and McGill University Centre for Translational Research in Cancer, Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada
Xiaohong Tian
Segal Cancer Center and McGill University Centre for Translational Research in Cancer, Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada
Qiang Liu
Segal Cancer Center and McGill University Centre for Translational Research in Cancer, Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada
Dinghong Qiu
Segal Cancer Center and McGill University Centre for Translational Research in Cancer, Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada
Mark Hancock
Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, QC H3G 1Y6, Canada
Jian Hui Wu
Segal Cancer Center and McGill University Centre for Translational Research in Cancer, Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC H4A 3T2, Canada; Corresponding author
Gerald Batist
Segal Cancer Center and McGill University Centre for Translational Research in Cancer, Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC H4A 3T2, Canada; Corresponding author
Summary: NRF2 (nuclear factor erythroid 2-related factor 2) is a master regulator of protective responses in healthy tissues. However, when it is active in tumor cells, it can result in drug resistance. KEAP1, the endogenous NRF2 inhibitor, binds NRF2 and redirects it to proteasomal degradation, so the KEAP1/NRF2 interaction is critical for maintaining NRF2 at a basal level. A number of clinically relevant KEAP1 mutations were shown to disrupt this critical KEAP1/NRF2 interaction, leading to elevated NRF2 levels and drug resistance. Here, we describe a small-molecule NRF2 inhibitor, R16, that selectively binds KEAP1 mutants and restores their NRF2-inhibitory function by repairing the disrupted KEAP1/NRF2 interactions. R16 substantially sensitizes KEAP1-mutated tumor cells to cisplatin and gefitinib, but does not do so for wild-type KEAP1 cells, and sensitizes KEAP1 G333C-mutated xenograft to cisplatin. We developed a BRET2-based biosensor system to detect the KEAP1/NRF2 interaction and classify KEAP1 mutations. This strategy would identify drug-resistant KEAP1 somatic mutations in clinical molecular profiling of tumors.
