RESUMO
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.
RESUMO
BACKGROUND: Refugee populations resettled in the United States face health disparities and barriers to accessing care. Better understanding of the barriers this population faces may help clinicians address them. METHODS: Focus groups with refugees were held in Wisconsin. Discussion prompts such as "What could be done to improve health in your community?" were used. Notes from the focus groups were organized and coded using MAXQDA. RESULTS: Six themes were identified from the focus groups regarding health care barriers and experiences: language, interpretation, pharmacy, insurance, transportation, and respect. DISCUSSION: Clinicians working with refugee populations can strive to minimize barriers to care for refugee patients by being aware of the barriers, implementing changes in their practice, and/or community advocacy.
