Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers.

Autor:	Wood K; Duke University., Nussbaum D; Duke University., Martz C; Duke University., Waters A; University of Cincinnati., Barrera A; Duke University., Rutter J; Duke University., Cerda-Smith C; Duke University., Stewart A; Duke University., Wu C; Memorial Sloan Kettering Cancer Center., Cakir M; Duke University., Levandowski C; University of Colorado., Kantrowitz D; Duke University., McCall S; Duke University., Pierobon M; Center for Applied Proteomics and Molecular Medicine, George Mason University., Petricoin E 3rd; George Mason University., Smith J; Memorial Sloan Kettering Cancer Center., Der C; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill., Taatjes D; University of Colorado.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Nov 02. Date of Electronic Publication: 2023 Nov 02.
DOI:	10.21203/rs.3.rs-3511242/v1
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. Competing Interests: Competing interests: KCW is a founder, consultant, and equity holder at Tavros Therapeutics and Celldom and has performed consulting work for Guidepoint Global, Bantam Pharmaceuticals, and Apple Tree Partners. CJD is an advisory board member for Deciphera Pharmaceuticals, Mirati Therapeutics, Reactive Biosciences, Revolution Medicines and SHY Therapeutics, has received research funding support from Deciphera Pharmaceuticals, Mirati Therapeutics, Reactive Biosciences, Revolution Medicines and SpringWorks Therapeutics, and has consulted for Day One Biotherapeutics, Eli Lilly, Jazz Therapeutics, Ribometrix, Sanofi, and Turning Point Therapeutics. The remaining authors declare no competing interests.
Databáze:	MEDLINE
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