MCB-613 exploits a collateral sensitivity in drug resistant EGFR -mutant non-small cell lung cancer through covalent inhibition of KEAP1 - Archive ouverte HAL Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2023

MCB-613 exploits a collateral sensitivity in drug resistant EGFR -mutant non-small cell lung cancer through covalent inhibition of KEAP1

Christopher Bassil
Gray Anderson
Kayleigh Askin
Peter Winter
Jacob Hoj
Christian Cerda-Smith
Rachid Benhida
Ann Marie Pendergast
Kris Wood

Résumé

ABSTRACT Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets EGFR -mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant, EGFR -mutant NSCLC cells.

Dates et versions

hal-04240243 , version 1 (13-10-2023)

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Christopher Bassil, Gray Anderson, Benjamin Mayro, Kayleigh Askin, Peter Winter, et al.. MCB-613 exploits a collateral sensitivity in drug resistant EGFR -mutant non-small cell lung cancer through covalent inhibition of KEAP1. 2023. ⟨hal-04240243⟩
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