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

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

PROVIDER: PRJNA630222 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11684830_1.fastq.gz	Fastqsanger.gz
	SRR11684830_2.fastq.gz	Fastqsanger.gz
	SRR11684831_1.fastq.gz	Fastqsanger.gz
	SRR11684831_2.fastq.gz	Fastqsanger.gz
	SRR11684832_1.fastq.gz	Fastqsanger.gz

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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

Rapid Idiosyncratic Mechanisms of Clinical Resistance to KRAS G12C Inhibition

Project description:Rapid Idiosyncratic Mechanisms of Clinical Resistance to KRAS G12C Inhibition

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Rapid Idiosyncratic Mechanisms of Clinical Resistance to KRAS G12C Inhibition

Project description:Rapid Idiosyncratic Mechanisms of Clinical Resistance to KRAS G12C Inhibition

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Genome-Wide CRISPR Screen Identifies Multiple Synthetic Lethal Targets That Enhance KRAS (G12C) Inhibitor Efficacy [CRISPR]

Project description:KRAS G12C inhibitors (G12Ci) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. KRAS plays a critical role in normal cell signaling; hence, G12Cis has been reported to create resistance. We found several novel pathways, including Hippo pathways, are enriched from significant dropouts upon MRTX849 treatment. Our results argue for testing KRAS G12C and TEAD inhibitor combinations in NSCLC patients.

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Project description:KRAS G12C inhibitors (G12Ci) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. KRAS plays a critical role in normal cell signaling; hence, G12Cis could influence the signaling pathways. We found that several novel pathways including Hippo pathways are upregulated upon MRTX849 treatment. Our results argue for testing KRAS G12C and TEAD inhibitor combinations in NSCLC patients.

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Genome-Wide CRISPR Screen Identifies Multiple Synthetic Lethal Targets That Enhance KRAS (G12C) Inhibitor Efficacy [RNA-seq-mm10]

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CRISPR-screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer

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Project description:To characterize sotorasib resistance in lung adenocarcinomas (LUAD), we generated genetically engineered mice (Kras-G12C, Trp53-KO) and compared the transcriptional profiles of untreated and sotorasib-resistant tumors

2023-03-05 | GSE204752 | GEO

Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC

Project description:SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion and promoted B and T lymphocyte infiltration in Kras- and Egfr- mutant non-small cell lung cancer (NSCLC). However, treatment also increased intratumor gMDSCs via tumor-intrinsic, NF-kB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C-inhibitor trials. Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster of S100a8/9high gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in NSCLC patients.

2021-07-29 | GSE180964 | GEO

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