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

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

PROVIDER: PRJNA981152 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24865901.fastq.gz	Fastqsanger.gz
	SRR24865902.fastq.gz	Fastqsanger.gz
	SRR24865903.fastq.gz	Fastqsanger.gz
	SRR24865904.fastq.gz	Fastqsanger.gz
	SRR24865905.fastq.gz	Fastqsanger.gz

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

Project description: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.

2024-06-26 | GSE234378 | GEO

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

Project description:Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/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

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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BCL6 is regulated by the RAS/MAPK/ELK axis and promotes KRAS-driven lung cancers

Project description:Mutational activation of KRAS represents a common oncogenic event in lung cancers and still lacks effective treatments so far. Here, we identify the proto-oncogene B-cell lymphoma 6 (BCL6) as a lynchpin for KRAS dependence. BCL6 transcription was markedly promoted upon inducible activation of KRAS in either LSL-KrasG12D mice lung tumor tissue or engineered KRAS isogenic cell lines. Constitutive expression of BCL6 was also observed in patients with KRAS-mutant lung adenocarcinoma and associated with poor survival. Employing chemical and genetic screens, we characterized that the MAPK/ELK1 axis downstream of KRAS directly regulated BCL6 expression. Genetic depletion or pharmacological inhibitor targeting BCL6 preferentially impedes the proliferation of KRAS-mutant lung cancer cells by suppressing pre-RC protein expression in cycling cells, ultimately leading to stalled replication and DNA damage in vitro. Accordingly, targeted inhibition of BCL6 significantly reduced tumor burden and mortality in LSL-KrasG12D/+ and patient-derived lung cancer xenograft mouse models in vivo. Taken together, these findings reveal an oncogenic role of BCL6 in promoting KRAS-addicted lung cancers and define that BCL6 inhibition confers a targetable vulnerability for this kind of disease.

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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 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.

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Project description:Pancreatic cancer is characterised by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered Kras gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic KRAS mutation is well characterised, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrate that wild-type Kras restrains the oncogenic impact of mutant Kras, and drastically impacts both Kras-mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increases oncogenic Kras signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated Myc levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type Kras sensitises Kras mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type Kras during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.

2024-09-22 | GSE277392 | GEO

CRAF dimerization with ARAF regulates KRAS driven tumors

Project description:KRAS, mutated in ~30% of all cancers, activates the RAF-MEK-ERK signaling cascade. It has previously been shown that CRAF is required for growth of KRAS mutant lung tumors but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescued growth inhibition suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrated enrichment of CRAF:ARAF dimers in KRAS mutant cells and depletion of both CRAF and ARAF rescued the CRAF loss phenotype. Mechanistically, CRAF depletion caused sustained ERK activation and induction of cell cycle arrest. Treatment with low dose MEK or ERK inhibitor rescued the CRAF loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting dimerization or degrading CRAF may have therapeutic benefit.

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Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function

Project description:Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function

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Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function

Project description:Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly understood. Here we show that KRASG12D expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRASG12D expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate lymphatic vessel maturation. We show that MEK1/2 inhibition with the FDA-approved drug trametinib suppresses KRASG12D-induced morphological changes, proliferation, and migration. Trametinib also decreases ERK1/2 phosphorylation and increases the expression of genes that regulate the maturation of lymphatic vessels. We also show that trametinib and Cre-mediated expression of a dominant-negative form of MEK1 (Map2k1K97M) suppresses KRASG12D-induced lymphatic vessel hyperplasia in embryos. Last, we demonstrate that conditional knockout of wild-type Kras in LECs does not affect the formation or function of lymphatic vessels. Together, our data indicate that KRAS/MAPK signaling must be tightly regulated during embryonic development for the proper development of lymphatic vessels and further support the testing of MEK1/2 inhibitors for treating CLAs.

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Project description:UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma

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