Mediator kinase inhibition impedes transcriptional plasticity and prevents resistance to ERK/MAPK-targeted therapy in KRAS-mutant cancers.

Autor: Nussbaum DP; Department of Surgery, Duke University School of Medicine, Durham, NC, USA., Martz CA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA., Waters AM; Department of Pharmacology, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA., Barrera A; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA., Liu A; Department of Surgery, Duke University School of Medicine, Durham, NC, USA., Rutter JC; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA., Cerda-Smith CG; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA., Stewart AE; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA., Wu C; Department of Surgery, Memorial Sloan Kettering Cancer Center, Colorectal Service, New York, NY, USA., Cakir M; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA., Levandowski CB; Department of Biochemistry, University of Colorado Boulder, Boulder, CO, USA., Kantrowitz DE; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA., McCall SJ; Department of Pathology, Duke University School of Medicine, Durham, NC, USA., Pierobon M; George Mason University, Center for Applied Proteomics and Molecular Medicine, Fairfax, VA, USA., Petricoin EF 3rd; George Mason University, Center for Applied Proteomics and Molecular Medicine, Fairfax, VA, USA., Joshua Smith J; Department of Surgery, Memorial Sloan Kettering Cancer Center, Colorectal Service, New York, NY, USA., Reddy TE; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA., Der CJ; Department of Pharmacology, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA., Taatjes DJ; Department of Biochemistry, University of Colorado Boulder, Boulder, CO, USA., Wood KC; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. kris.wood@duke.edu.
Jazyk: angličtina
Zdroj: NPJ precision oncology [NPJ Precis Oncol] 2024 May 31; Vol. 8 (1), pp. 124. Date of Electronic Publication: 2024 May 31.
DOI: 10.1038/s41698-024-00615-9
Abstrakt: Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and cell line-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, cell line-specific resistance programs.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: