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SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-dependent Tumors

ABSTRACT: SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-dependent Tumors

PROVIDER: PRJNA495756 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8003862.fastq.gz	Fastqsanger.gz
	SRR8003863.fastq.gz	Fastqsanger.gz
	SRR8003864.fastq.gz	Fastqsanger.gz
	SRR8003865.fastq.gz	Fastqsanger.gz
	SRR8003866.fastq.gz	Fastqsanger.gz

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Similar Datasets

SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-dependent Tumors

Project description:We performed RNA sequencing analysis using NextSeq500 to identify drivers that mediate feedback RAS activation in BRAF(V600E) cells that are SHP2 independent.

2018-10-12 | GSE121117 | GEO

SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors.

Project description:Pharmacologic targeting of components of ERK signaling in ERK-dependent tumors is often limited by adaptive resistance, frequently mediated by feedback-activation of RTK signaling and rebound of ERK activity. Here, we show that combinatorial pharmacologic targeting of ERK signaling and the SHP2 phosphatase prevents adaptive resistance in defined subsets of ERK-dependent tumors. In each tumor that was sensitive to combined treatment, p(Y542)SHP2 induction was observed in response to ERK signaling inhibition. The strategy was broadly effective in TNBC models and tumors with RAS mutations at G12, whereas tumors with RAS(G13D) or RAS(Q61X) mutations were resistant. In addition, we identified a subset of BRAF(V600E) tumors that were resistant to the combined treatment, in which FGFR was found to drive feedback-induced RAS activation, independently of SHP2. Thus, we identify molecular determinants of response to combined ERK signaling and SHP2 inhibition in ERK-dependent tumors.

| S-EPMC6396678 | biostudies-literature

Molecularly defined circuits for cardiovascular and cardiopulmonary control

Project description:Molecularly defined circuits for cardiovascular and cardiopulmonary control

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Tyr62 phosphorylation of the phosphatase SHP2 enables acquired resistance to SHP2 allosteric inhibitors in FLT3-ITD-driven AML

Project description:The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases (RTKs), as it is required for full RAS-ERK activation to promote cell proliferation and survival programs. SHP2 allosteric inhibitors act by stabilizing SHP2 in its auto-inhibited conformation and they are currently being tested in clinical trials for tumors with over-activation of the RAS/ERK pathway, alone and in various drug combinations. Using in vitro models, we established acquired resistant cell lines to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD-positive AML cell lines. We performed both label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics to reveal that AML cells can restore phosphorylated ERK (pERK) in presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induces the tyrosine phosphorylation and feedback-activation of the FLT3 receptor, which in turn phosphorylates SHP2 on Tyrosine 62. This phosphorylation stabilizes SHP2 in its open conformation, preventing SHP099 binding, thus resulting in resistance. Combinatorial inhibition of SHP2 and MEK or SHP2 and FLT3 prevents pERK rebound and resistant cell growth. We observed the same mechanism in a FLT3-mutated B-ALL cell line and in the inv(16)/KITD816Y AML mouse model. Finally, we show that allosteric SHP2 inhibition does not impair the clonogenic ability of normal bone marrow progenitors, supporting its future use for clinical applications.

2023-03-10 | PXD030338 | Pride

SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms

Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1+, but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.

2017-06-06 | GSE99656 | GEO

Morphological diversity of single neurons in molecularly defined cell types

Project description:Morphological diversity of single neurons in molecularly defined cell types

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Molecularly defined and functionally distinct subcircuits of the medial mammillary nucleus

Project description:Molecularly defined and functionally distinct subcircuits of the medial mammillary nucleus

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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

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

Shp2 transcriptome in melanoma

Project description:1205Lu Metastatic Human melanoma cell lines with knockdown of Shp2 (PTPN11) were grown as xenograft tumors in NSG mice. RNA was extracted from the tumors and analyzed on [HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version] Shp2 knockdown compared with non-target controls

2016-07-03 | E-GEOD-53282 | biostudies-arrayexpress

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