| Autor: |
Christopher F. Bassil, Gray R. Anderson, Benjamin Mayro, Kayleigh N. Askin, Peter S. Winter, Samuel Gruber, Tierney M. Hall, Jacob P. Hoj, Christian Cerda-Smith, Haley M. Hutchinson, Shane T. Killarney, Katherine R. Singleton, Li Qin, Kévin Jubien-Girard, Cécile Favreau, Anthony R. Martin, Guillaume Robert, Rachid Benhida, Patrick Auberger, Ann Marie Pendergast, David M. Lonard, Alexandre Puissant, Kris C. Wood |
| Rok vydání: |
2023 |
| Popis: |
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 targetsEGFR-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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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