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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 [RNA-seq]

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

PROVIDER: PRJNA665977 | 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

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

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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.

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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 [RNA-seq]

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

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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.

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