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RUNX2/CBFB modulates the response to MEK inhibitors through activation of receptor tyrosine kinases in KRAS mutant colorectal cancer

ABSTRACT: RUNX2/CBFB modulates the response to MEK inhibitors through activation of receptor tyrosine kinases in KRAS mutant colorectal cancer

PROVIDER: PRJNA578685 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10317217.fastq.gz	Fastqsanger.gz
	SRR10317218.fastq.gz	Fastqsanger.gz
	SRR10317219.fastq.gz	Fastqsanger.gz
	SRR10317220.fastq.gz	Fastqsanger.gz
	SRR10317221.fastq.gz	Fastqsanger.gz

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RUNX2/CBFB modulates the response to MEK inhibitors through activation of receptor tyrosine kinases in KRAS mutant colorectal cancer

Project description:Investigation of the transcriptional consequences of RUNX2 and CBFB loss in the presence and absence of the MEK inhibitor selumetinib in LoVo ERN1 knockout KRAS mutant colorectal cancer cells.

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RUNX2 and CBFB genome-wide binding in osteosarcoma SAOS2 cells

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RUNX2/CBFB modulates the response to MEK inhibitors through activation of receptor tyrosine kinases in KRAS-mutant colorectal cancer.

Project description:Intrinsic and acquired resistances are major hurdles preventing the effective use of MEK inhibitors for treatment of colorectal cancer (CRC). Some 35-45% of colorectal cancers are KRAS-mutant and their treatment remains challenging as these cancers are refractory to MEK inhibitor treatment, because of feedback activation of receptor tyrosine kinases (RTKs). We reported previously that loss of ERN1 sensitizes a subset of KRAS-mutant colon cancer cells to MEK inhibition. Here we show that the loss of RUNX2 or its cofactor CBFB can confer MEK inhibitor resistance in CRC cells. Mechanistically, we find that cells with genetically ablated RUNX2 or CBFB activate multiple RTKs, which coincides with high SHP2 phosphatase activity, a phosphatase that relays signals from the cell membrane to downstream pathways governing growth and proliferation. Moreover, we show that high activity of SHP2 is causal to loss of RUNX2-induced MEK inhibitor resistance, as a small molecule SHP2 inhibitor reinstates sensitivity to MEK inhibitor in RUNX2 knockout cells. Our results reveal an unexpected role for loss of RUNX2/CBFB in regulating RTK activity in colon cancer, resulting in reduced sensitivity to MEK inhibitors.

| S-EPMC6931198 | biostudies-literature

Reduced Proteolytic Shedding of Receptor Tyrosine Kinases is a Post-Translational Mechanism of Kinase Inhibitor Resistance.

Project description:Expression data from MDA-MB231 human breast cancer cells treated with metalloproteinase inhibitor (10uM BB94), MEK inhibitor (3uM PD325901), or DMSO control shows substantial overlap in the transcriptional responses arising from MEK and protease inhibition, suggesting a shared mechanism of action. Kinase inhibitor resistance often involves upregulation of poorly understood “bypass” signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTKs) including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of melanoma patients treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured non-invasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.

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Profiling uterine fibroid specimens with an in-house array representing all 90 human tyrosine kinases and their ligands

Project description:The aim of this study is to compare the expression patterns of tyrosine kinases and their ligand activators between matched myometrium and leiomyoma tissues. For this, total RNA samples extracted from 42 pairs of matched fibroid and adjacent myometrial tissues were hybridized to a set of 840 customized oligonucleotide microarrays to compare the expression profiles of 244 selected human genes including all 90 tyrosine kinases and 103 ligands. Among the 244 genes surveyed, 38 were found to be differentially expressed between pairs of myometrium and fibroid tissues. Clustering analysis of the expression ratios of these 38 genes from 42 pairs of samples has led to the subdivision of fibroid samples into three groups, based on the expression ratios of two peptide ligands, CYR61 and EFNA4. Real-time quantitative RT-PCR measurements of additional 32 pairs of samples further confirmed the existence of these three groups of fibroid samples. In conclusion, peptide ligand activators of protein tyrosine kinases are differentially expressed between myometrium and fibroid tissues. This finding supports the notion that tyrosine kinases may be exploited as medical targets to treat symptomatic fibroids without surgical intervention.Â Â This study has been accomplished with 42 patients fibroid specimen and their matched myometrium, each pair of specimen has been repeated at least 3 times.

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Receptor Tyrosine Kinases phosphorylate RNA polymerase II at signal-responsive genes

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Profiling uterine fibroid specimens with an in-house array representing all 90 human tyrosine kinases and their ligands

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Cbfb/Runx1-repression independent blockage of differentiation and accumulation of Csf2rb expressing cells by Cbfb-MYH11

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