MCB-613 exploits a collateral sensitivity in drug resistant EGFR -mutant non-small cell lung cancer through covalent inhibition of KEAP1.
Christopher F BassilGrace R AndersonBenjamin MayroKayleigh N AskinPeter S WinterSamuel GruberTierney M HallJacob P HojChristian G Cerda-SmithHaley M HutchinsonShane T KillarneyKatherine R SingletonLi QinKévin Jubien-GirardCécile FavreauAnthony R MartinGuillaume RobertRachid BenhidaPatrick AubergerAnn Marie PendergastDavid M LonardAlexandre PuissantKris C WoodPublished in: bioRxiv : the preprint server for biology (2023)
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.
Keyphrases
- drug resistant
- small cell lung cancer
- induced apoptosis
- protein protein
- epidermal growth factor receptor
- small molecule
- high throughput
- multidrug resistant
- tyrosine kinase
- single molecule
- acinetobacter baumannii
- cell cycle arrest
- oxidative stress
- advanced non small cell lung cancer
- endoplasmic reticulum stress
- brain metastases
- signaling pathway
- genome wide
- ejection fraction
- copy number
- newly diagnosed
- squamous cell carcinoma
- gene expression
- emergency department
- locally advanced
- living cells
- pseudomonas aeruginosa
- drug induced
- prognostic factors
- lymph node metastasis
- papillary thyroid
- rectal cancer