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Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment

ABSTRACT: Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment

PROVIDER: PRJNA1023194 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26253604_1.fastq.gz	Fastqsanger.gz
	SRR26253604_2.fastq.gz	Fastqsanger.gz
	SRR26253605_1.fastq.gz	Fastqsanger.gz
	SRR26253605_2.fastq.gz	Fastqsanger.gz
	SRR26253606_1.fastq.gz	Fastqsanger.gz

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Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment

Project description:Background: KRAS mutation is one of the most common oncogenic drivers in NSCLC, however, the response to immunotherapy is heterogeneous owing to the distinct co-occurring genomic alterations. KRAS/LKB1 co-mutated lung adenocarcinoma displays poor response to PD-1 blockade whereas the mechanism remains undetermined. Methods: We explored the specific characteristics of tumor microenvironment (TME) in KL tumors using syngeneic KRASG12DLKB1-/-(KL) and KRASG12DTP53-/- (KP) lung cancer mouse models. The impact of focal adhesion kinase (FAK) inhibitor on KL lung tumors was investigated in vitro and in vivo through evaluation of both KL cell lines and KL lung cancer mouse models. Results: We identified KL tumors as “immune-cold” tumors with excessive extracellular matrix (ECM) collagen deposition that formed a physical barrier to block the infiltration of CD8+T cells. Mechanistically, abundant activated cancer-associated fibroblasts (CAFs) resulted from FAK activation contributed to the formation of the unique TME of KL tumors. FAK inhibition with a small molecular inhibitor could remodel the TME by inhibiting CAFs activation, decreasing collagen deposition and further facilitating the infiltration of anti-tumor immune cells, including CD8+ T cells, DC cells and M1-like macrophages into tumors, hence, converting “immune-cold” KL tumors into “immune-hot” tumors. The combined FAK inhibitor and PD-1 blockade therapy synergistically retarded primary and metastatic tumor growth of KL tumors.Conclusions: Our study identified FAK as a promising intervention target for KL tumors and provided basis for the combination of FAK inhibitor with PD-1 blockade in the management of KL lung cancers.

2024-02-07 | GSE244452 | GEO

Focal Adhesion Kinase Dependent Expression

Project description:The goal of this study was to identify transcripts, which are differentially regulatulated in the presence and absence of Focal Adhesion Kinase. As Focal Adhesion Kinase activity can depend upon cell density (Snijder et al. Nature 2009), biological replicates where cells, were seeded very sparsely or confluently, were used. Focal Adhesion Kinase Knockout (ATCC CRL-2644) and Rescue Cells (Sieg et al. 1998, clone DA2) were seeded at two different concentrations. Replicas refer to biological replicates, performed on different days. Only one single technical replicate has been done per biological replicate.

2013-09-17 | E-GEOD-43873 | biostudies-arrayexpress

Focal Adhesion Kinase Dependent Expression

2013-09-17 | GSE43873 | GEO

Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment.

Project description:BackgroundKRAS mutation is one of the most common oncogenic drivers in NSCLC, however, the response to immunotherapy is heterogeneous owing to the distinct co-occurring genomic alterations. KRAS/LKB1 co-mutated lung adenocarcinoma displays poor response to PD-1 blockade whereas the mechanism remains undetermined.MethodsWe explored the specific characteristics of tumor microenvironment (TME) in KL tumors using syngeneic KRASG12DLKB1-/- (KL) and KRASG12DTP53-/- (KP) lung cancer mouse models. The impact of focal adhesion kinase (FAK) inhibitor on KL lung tumors was investigated in vitro and in vivo through evaluation of both KL cell lines and KL lung cancer mouse models.ResultsWe identified KL tumors as "immune-cold" tumors with excessive extracellular matrix (ECM) collagen deposition that formed a physical barrier to block the infiltration of CD8+T cells. Mechanistically, abundant activated cancer-associated fibroblasts (CAFs) resulted from FAK activation contributed to the formation of the unique TME of KL tumors. FAK inhibition with a small molecular inhibitor could remodel the TME by inhibiting CAFs activation, decreasing collagen deposition and further facilitating the infiltration of anti-tumor immune cells, including CD8+ T cells, DC cells and M1-like macrophages into tumors, hence, converting "immune-cold" KL tumors into "immune-hot" tumors. The combined FAK inhibitor and PD-1 blockade therapy synergistically retarded primary and metastatic tumor growth of KL tumors.ConclusionsOur study identified FAK as a promising intervention target for KL tumors and provided basis for the combination of FAK inhibitor with PD-1 blockade in the management of KL lung cancers.

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