MCB-613 exploits a collateral sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer through covalent inhibition of KEAP1
Bassil, C. F.; Anderson, G. R.; Mayro, B.; Askin, K. N.; Winter, P. S.; Gruber, S.; Hall, T. M.; Hoj, J. P.; Cerda-Smith, C.; Hutchinson, H. M.; Killarney, S. T.; Singleton, K. R.; Qin, L.; Jubien-Girard, K.; Favreau, C.; Martin, A. R.; Robert, G.; Benhida, R.; Auberger, P.; Pendergast, A. M.; Lonard, D. M.; Puissant, A.; Wood, K. C.
Show 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.
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