Dissecting KEAP1-NRF2 interactions: Structural and functional impact of cancer-associated KEAP1 mutants

This preprint characterises three cancer-associated KEAP1 mutants, R470C, G480W and R554Q, by thermal shift, microscale thermophoresis, isothermal calorimetry and crystallography, and frames constitutive NRF2 activation as a driver of tumour growth, chemoresistance and metabolic reprogramming. The Claidex graph holds one NFE2L2 failure, mgy825-nfe2l2-nrf2-mutant-nsclc-phase1-strategic-termination, a Phase 1 of MGY825 in advanced NFE2L2, KEAP1 or CUL3 mutant non-small cell lung cancer, terminated on a business decision with no stated safety concern. The prior trial and this preprint address the same axis in overlapping mutational classes, but the termination was strategic rather than mechanistic, so severity is mild. The allele-by-allele resolution reported here is exactly the stratification that a trial enrolling a whole mutation class does not apply, and it is the variable worth carrying into any successor study.