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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 [single-cell RNA-seq]

ABSTRACT: 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]

PROVIDER: PRJNA665978 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12720583_1.fastq.gz	Fastqsanger.gz
	SRR12720583_2.fastq.gz	Fastqsanger.gz
	SRR12720584_1.fastq.gz	Fastqsanger.gz
	SRR12720584_2.fastq.gz	Fastqsanger.gz
	SRR12720585_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

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

| PRJNA665973 | 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: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 [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 [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 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

In vitro drug screening of RAF/MEK/ERK Inhibitors in two PDA Cell Lines

Project description:In this study 14 different RAF, MEK, or ERK inhibitors were tested in ASPC1 and PANC1 PDA cell lines

2024-04-28 | GSE252002 | 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

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