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

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...

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Published in:NPJ precision oncology 2024-05, Vol.8 (1), p.124-14, Article 124
Main Authors: Nussbaum, Daniel P., Martz, Colin A., Waters, Andrew M., Barrera, Alejandro, Liu, Annie, Rutter, Justine C., Cerda-Smith, Christian G., Stewart, Amy E., Wu, Chao, Cakir, Merve, Levandowski, Cecilia B., Kantrowitz, David E., McCall, Shannon J., Pierobon, Mariaelena, Petricoin, Emanuel F., Joshua Smith, J., Reddy, Timothy E., Der, Channing J., Taatjes, Dylan J., Wood, Kris C.
Format: Article
Language:English
Subjects:
631/67/1059/2325
631/67/1059/602
Cancer Research
Cell cycle
Cell growth
Epigenetics
Feedback
Gene Therapy
Human Genetics
Internal Medicine
Kinases
Lung cancer
Medicine
Medicine & Public Health
Oncology
Phosphorylation
Proteins
Tumors
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Summary: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.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-024-00615-9