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

ABSTRACT: Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS, for example, 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 second-generation MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, 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 tumor-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 sustained 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, tumor-specific resistance programs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234378 | GEO | 2024/06/26

REPOSITORIES: GEO

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

Project description: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 tumor-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved population-level 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, tumor-specific resistance programs.

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2014-07-27 | E-GEOD-56175 | biostudies-arrayexpress

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

Project description:Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to Sustained MAPK-Targeted Therapy in KRAS-Mutant Cancers

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

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Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling. We used microarrays to compare gene expression in HCT116 cells in which we suppressed KRAS expression doxycycline-inducible shRNA targeting KRAS compared to cells treated with media alone (no shKRAS induced). We express KRAS, LacZ, and YAP1 in each condition to identify genes transcriptionally involved in the rescue of KRAS suppression. HCT116 cells harboring doxycycline-inducible shKRAS (HCTtetK) expressing either LacZ, KRAS, or YAP1, were treated with doxycycline for 30 hours to suppress KRAS. Untreated (no doxycycline) cells expressing each ORF were used as control. Total RNA was collected using PerfectPure RNA Cultured Cell Kit (5Prime) and expression profiling was performed on Human Genome U133A 2.0 Array (Affymetrix) using the Dana Farber Cancer Institute Microarray Core.

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