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Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity

ABSTRACT: Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity

PROVIDER: PRJNA665973 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12720519_1.fastq.gz	Fastqsanger.gz
	SRR12720519_2.fastq.gz	Fastqsanger.gz
	SRR12720520_1.fastq.gz	Fastqsanger.gz
	SRR12720520_2.fastq.gz	Fastqsanger.gz
	SRR12720521_1.fastq.gz	Fastqsanger.gz

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Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [TCR-seq]

Project description:Disruption of the MAPK pathway in cancer by kinase inhibition often fails due to pathway reactivation, causing clinical relapse. Among MAPK inhibitors, type I RAF inhibitors are only active against specific BRAF mutants; MEK inhibitor monotherapy is associated with limited clinical benefits but may serve as a foundation for combinatorial therapy. Here, we show that type II RAF plus allosteric MEK inhibitors durably blunt the development of acquired MEK inhibitor resistance among cancers with KRAS, NRAS, NF1, BRAFnon-V600 and BRAFV600 mutations, when compared to a combination of type II RAF plus ERK inhibitors. Type II RAF and MEK (versus ERK) inhibitors also display superior capacity to sequester MEK in RAF complexes and uncouple MEK and ERK interaction in acquired resistant tumor subpopulations. Systemically and intratumorally, type II RAF plus MEK inhibitors expand memory and activated/exhausted CD8+ T-cells. Whereas trametinib alone temporally reduces dominant intra-tumoral T-cell clones, type II RAF inhibitor co-treatment reverses this effect and promotes T-cell clonotypic expansion and convergence. Importantly, durably control of tumors by this combination requires CD8+ T-cells. Thus, the prolonged anti-tumor efficacy of type II RAF plus MEK inhibitors reveals exquisite MAPK addiction in common lethal cancer histologies, and the mechanisms include unexpected allosteric perturbation of the MAPK pathway and engagement of anti-tumor CD8+ T-cell immunity.

2021-06-06 | GSE158608 | GEO

Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [RNA-seq]

2021-06-06 | GSE158607 | GEO

Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [single-cell RNA-seq]

2021-06-06 | GSE158609 | GEO

Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [RNA-seq]

Project description:Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [RNA-seq]

| PRJNA665977 | ENA

Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [TCR-seq]

Project description:Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [TCR-seq]

| PRJNA665976 | ENA

Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [single-cell RNA-seq]

Project description:Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [single-cell RNA-seq]

| PRJNA665978 | ENA

Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity.

Project description:MAPK targeting in cancer often fails due to MAPK reactivation. MEK inhibitor (MEKi) monotherapy provides limited clinical benefits but may serve as a foundation for combination therapies. Here, we showed that combining a type II RAF inhibitor (RAFi) with an allosteric MEKi durably prevents and overcomes acquired resistance among cancers with KRAS, NRAS, NF1, BRAF non-V600, and BRAF V600 mutations. Tumor cell-intrinsically, type II RAFi plus MEKi sequester MEK in RAF complexes, reduce MEK/MEK dimerization, and uncouple MEK from ERK in acquired-resistant tumor subpopulations. Immunologically, this combination expands memory and activated/exhausted CD8+ T cells, and durable tumor regression elicited by this combination requires CD8+ T cells, which can be reinvigorated by anti-PD-L1 therapy. Whereas MEKi reduces dominant intratumoral T-cell clones, type II RAFi cotreatment reverses this effect and promotes T-cell clonotypic expansion. These findings rationalize the clinical development of type II RAFi plus MEKi and their further combination with PD-1/L1-targeted therapy. SIGNIFICANCE: Type I RAFi + MEKi are indicated only in certain BRAF V600MUT cancers. In contrast, type II RAFi + MEKi are durably active against acquired MEKi resistance across broad cancer indications, which reveals exquisite MAPK addiction. Allosteric modulation of MAPK protein/protein interactions and temporal preservation of intratumoral CD8+ T cells are mechanisms that may be further exploited.This article is highlighted in the In This Issue feature, p. 521.

| S-EPMC7933113 | biostudies-literature

Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-06-06 | GSE158610 | GEO

TNF-a-induced MEK/ERK-dependent regulation of Cartilage Matrix Genes

Project description:TNF-a is increased in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. TNF-a activates MEK/ERK in chondrocytes; however the overall functional relevance of MEK/ERK to TNF-a-regulated gene expression in chondrocytes is unknown. Chondrocytes were treated with TNF-a with or without the MEK1/2 inhibitor U0126 for 24 h. Microarray analysis was used to identify genes regulated by TNF-a in a MEK1/2-dependent fashion. Keywords: compound, signalling response

2009-01-14 | GSE14402 | GEO

Nitrosylation-mediated regulation of MEK-ERK signaling in the NRAS-mutant melanoma

Project description:NRAS activating mutations occur in 15-25% of melanoma patients. However, this subtype is more aggressive and refractory to current treatment modalities, including targeted MEK inhibitors, immunotherapies, and the recently emerging RAS inhibitors. Accordingly, identifying novel therapeutic targets and designing novel antimelanoma strategies is of utmost clinical relevance. Melanomas often harbor hyperactive nitric oxide synthases (NOS) which correlates strongly with poor prognosis. NOS is also known to be activated by ERK signaling. The nitric oxide so produced, induces nitrosylation, a post-translational modification, which dysregulates various kinases and phosphatases. We sensitized NRAS-mutant melanomas to targeted MEK inhibitors by inhibiting nitrosylation. This outcome revealed a strong correlation between global de-nitrosylation and downregulation of MEK-ERK cascade with a concomitant de-nitrosylation of NRAS and other small GTPases like Rho and Rac, dual specificity phosphatases, and ribosomal S6 kinase. In vivo, we observed extreme regression of NRAS-mutant melanoma tumors generated in an immunocompetent mouse model in response to a sequential nitrosylation inhibition and MEK inhibition. In addition to MEK-ERK downregulation, this strategy activated the CD8+ T cells in the tumor microenvironment. We conclude that while nitrosylation hyperactivates the RAS-RAF-MEK-ERK cascade, it also suppresses anti-melanoma immune response, bolstering progression and MEKi resistance. The underlying mechanism(s) will be crucial in identifying novel therapeutic vulnerabilities against aggressive, currently incurable NRAS-mutant melanomas with potential clinical application in other melanoma subtypes.

2025-05-02 | PXD050244 | Pride

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