MCB-613 exploits a collateral sensitivity in drug resistant EGFR -mutant non-small cell lung cancer through covalent inhibition of KEAP1.
| العنوان: | MCB-613 exploits a collateral sensitivity in drug resistant EGFR -mutant non-small cell lung cancer through covalent inhibition of KEAP1. |
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| المؤلفون: | Bassil CF; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Anderson GR; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Mayro B; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Askin KN; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Winter PS; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Gruber S; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Hall TM; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Hoj JP; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Cerda-Smith C; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Hutchinson HM; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Killarney ST; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Singleton KR; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Qin L; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA., Jubien-Girard K; Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272 - 06108 Nice, France., Favreau C; Université Côte d'Azur, INSERM, C3M, Nice, France., Martin AR; Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272 - 06108 Nice, France.; IBMM, Université de Montpellier, ENSCM, CNRS, Montpellier, France., Robert G; Université Côte d'Azur, INSERM, C3M, Nice, France., Benhida R; Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272 - 06108 Nice, France.; Chemical & Biochemical Sciences Green-Process Engineering (CBS) Mohammed VI Polytechnic University, Lot 660, Hay Moulay Rachid, Benguerir, Morocco., Auberger P; Université Côte d'Azur, INSERM, C3M, Nice, France., Pendergast AM; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Lonard DM; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA., Puissant A; Université de Paris, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, Paris, France., Wood KC; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Jan 19. Date of Electronic Publication: 2023 Jan 19. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | 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. Competing Interests: COMPETING INTERESTS K.C.W. is a founder, consultant, and equity holder at Tavros Therapeutics and Celldom, an equity holder at Decrypt Bio and Simple Therapeutics, and has performed consulting work for Guidepoint Global, Bantam Pharmaceuticals, and Apple Tree Partners. D.M.L. is a paid consultant and holds an equity position in CoRegen, Inc., a biotechnology company developing MCB-613 for clinical use. |
| معلومات مُعتمدة: | T32 GM007171 United States GM NIGMS NIH HHS; T32 GM145449 United States GM NIGMS NIH HHS |
| تواريخ الأحداث: | Date Created: 20230130 Latest Revision: 20231019 |
| رمز التحديث: | 20231020 |
| مُعرف محوري في PubMed: | PMC9882253 |
| DOI: | 10.1101/2023.01.17.524094 |
| PMID: | 36711936 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.01.17.524094 |
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