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Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [RNA-seq]

ABSTRACT: Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [RNA-seq]

PROVIDER: PRJNA1049461 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27118137_1.fastq.gz	Fastqsanger.gz
	SRR27118137_2.fastq.gz	Fastqsanger.gz
	SRR27118138_1.fastq.gz	Fastqsanger.gz
	SRR27118138_2.fastq.gz	Fastqsanger.gz
	SRR27118139_1.fastq.gz	Fastqsanger.gz

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Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models.

Project description:Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models.

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Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [CRISPR]

Project description:Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [CRISPR]

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Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [DSP]

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Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [scRNA-seq]

Project description:Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [scRNA-seq]

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Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [DSP]

Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which new therapeutic interventions are needed. Here, we assessed the cellular response to pharmacological KRAS inhibition, targeting the central oncogenic factor in PDAC. In a panel of PDAC cell lines, pharmaceutical inhibition of the KRASG12D allele with MRTX1133 yields variable efficacy in the suppression of cell growth and downstream gene expression programs in 2D culture. CRISPR-Cas9 loss-of-function screens identified ITGB1 as a novel driver for enhanced therapeutic response that regulates mechanotransdcution signaling and YAP/TAZ expression, which is further confirmed by gene specific knockdowns and combinatorial drug synergy. Interestingly, MRTX1133 is considerably more efficacious in the context of 3D cell cultures. Moreover, MRTX1133 elicits a more pronounced cytostatic effect in controlling the in vivo tumor growth in PDAC patient-derived xenografts. In syngeneic models, KRASG12D inhibition leads to potent tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicates that MRTX1133-mediated KRAS inhibition enhances interferon-γ signaling and induces antigen presentation that modulates the tumor microenvironment. Further investigation on the immunological response using single-cell sequencing and multispectral imaging reveals that tumor regression is associated with suppression of neutrophils and influx of effector CD8+ T-cells. Thus, both tumor cell-intrinsic and extrinsic events contribute to response and credential KRASG12D inhibition as a promising strategy for a large percentage of PDAC tumors.

2024-01-24 | GSE249538 | GEO

Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [CRISPR]

2024-01-24 | GSE249537 | GEO

Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [scRNA-seq]

2024-01-24 | GSE249540 | GEO

Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [RNA-seq]

2024-01-24 | GSE249539 | GEO

SHP2 Inhibition Abrogates Adaptive Resistance to KRAS-G12C-Inhibition and Remodels the Tumor Microenvironment of KRAS-Mutant Tumors

Project description:KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime goal. Recently, inhibitors (G12C-Is) that bind KRAS-G12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRAS-G12C activation and inhibitor engagement, we found that SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRAS-G12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models. The combination of SHP2-I and G12C-I evoked favorable changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using an inhibitor-resistant SHP2 mutant showed that SHP2 inhibition in PDAC cells is required for tumor regression and remodeling of the immune microenvironment, but SHP2-Is also had direct effects on angiogenesis. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies. G12C-Is show significant, but limited, efficacy as single agents, in part because of “adaptive resistance”. We find that combining G12C-Is with SHP2-Is abrogates adaptive resistance and results in favorable changes in the immune microenvironment that potentiate PD-1 blockade in KRAS-mutant malignancies. SHP2-Is also can have direct, context-dependent, effects on tumor vasculature.

2020-10-01 | GSE149815 | GEO

Radiation combined with KRAS-MEK inhibitors enhances anticancer immunity in KRAS-mutated tumor models [LLC RNA-seq]

Project description:KRAS mutation is a common driver in solid tumors, and KRAS-mutated tumors are relatively resistant to radiotherapy. Therefore, we investigated the combined effect of radiation and KRAS-MEK inhibitors (AMG510 and trametinib) in KRAS-mutated tumors.

2022-10-01 | GSE209766 | GEO

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