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

   

Authors:	Nussbaum, D. P.; Martz, C. A.; Waters, A. M.; Barrera, A.; Liu, A.; Rutter, J. C.; Cerda-Smith, C. G.; Stewart, A. E.; Wu, C.; Cakir, M.; Levandowski, C. B.; Kantrowitz, D. E.; McCall, S. J.; Pierobon, M.; Petricoin, E. F. 3rd; Smith, J. J.; Reddy, T. E.; Der, C. J.; Taatjes, D. J.; Wood, K. C.
Article Title:	Mediator kinase inhibition impedes transcriptional plasticity and prevents resistance to ERK/MAPK-targeted therapy in KRAS-mutant cancers
Abstract:	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. © The Author(s) 2024.
Keywords:	signal transduction; controlled study; protein expression; treatment response; nonhuman; cell proliferation; animal cell; mouse; phenotype; gene expression; animal experiment; lung cancer; phosphorylation; tumor growth; drug sensitivity; phosphotransferase; akt signaling; mapk signaling; human; article; differential gene expression; pancreatic cancer cell line
Journal Title:	npj Precision Oncology
Volume:	8
ISSN:	2397-768X
Publisher:	Springer Nature
Date Published:	2024-05-31
Start Page:	124
Language:	English
DOI:	10.1038/s41698-024-00615-9
PROVIDER:	scopus
PMCID:	PMC11143207
PUBMED:	38822082
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85194862385&doi=10.1038%2fs41698-024-00615-9&partnerID=40&md5=5a29f98a58a000a1ea2bc12a241ade31
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/216939