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Inhibition of Met results in concomitant inhibition of Akt and STAT3 signaling pathways, while abrogation of negative feedback permits Erk reactivation

ABSTRACT: Amplification and activation of the Met receptor tyrosine kinase occurs up to 23% of gastric cancers, suggesting that Met is a therapeutic target in these cancers. However, the steady-state signaling events that occur during chronic Met activation, and mechanisms for resistance to Met small-molecule inhibitors, are poorly understood. Here we show that multiple gastric cancer cell lines harboring MET amplifications are dependent on Met signaling for proliferation and anchorage-independent growth. In these cells, short-term inhibition of Met leads to coordinated changes in gene expression; these include a rapid loss in expression of immediate-early genes, followed by decreased expression of genes involved in cell cycle and proliferation. Activation of Ras-Erk, PI3K-Akt and STAT3 pathways is attenuated by acute Met inhibition. STAT3 inhibition alone, but not individual inhibition of Mek or Akt, is sufficient to abrogate Met-dependent growth of these cells. However, following chronic Met inhibition, reactivation of Mek-dependent Erk phosphorylation occurs even in the presence of Met inhibitor corresponding with a downregulation of Erk negative regulators DUSP4/6. This provides a mechanism for the emergence of drug resistance. Our findings provide insights into innate resistance to a small-molecule Met inhibitor and highlight rational combination therapies that could be evaluated in clinical trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54532 | GEO | 2014/05/19

SECONDARY ACCESSION(S): PRJNA237003

REPOSITORIES: GEO

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Project description:Identification of MEK-ERK or p38MAPK dependent genes in human monocyte derived dendritic cells. Dendritic cells (DC) promote tolerance or immunity depending on their maturation state. Previous studies have revealed that DC maturation is enhanced or accelerated upon MEK-ERK signaling pathway inhibition. We have now determined the contribution of MEK-ERK activation to the profile of gene expression of human immature monocyte-derived dendritic cells (MDDC) and peripheral blood myeloid DC. ERK inhibition altered the expression of genes that mediate CCL19-directed migration (CCR7) and LDL binding (CD36, SCARB1, OLR1, CXCL16) by immature DC. Besides, ERK upregulated CCL2 expression while impaired the expression of DC maturation markers (RUNX3, ITGB7, IDO1). MEK-ERK-regulated genes exhibited an over-representation of cognate sequences for the Aryl Hydrocarbon Receptor (AhR) transcription factor, and we show that AhR mediates some of the ERK-dependent transcriptional effects in DC. Therefore, MEK-ERK signaling pathway regulates antigen capture, lymph node homing and the acquisition of maturation-associated genes, and its contribution to the maintenance of the immature state of MDDC and myeloid DC is partly dependent on the activity of AhR. Since pharmacological modulation of the MEK-ERK signaling pathway has been proposed as a potential therapeutic strategy for cancer, our findings indicate that ERK inhibitors might influence the generation of anti-tumor responses through regulation of critical DC effector functions. Human peripheral blood monocytes from three independent healthy donors (DC4, DC5 and DC7) were isolated by anti-CD14-labeled magnetic microbeads. CD14+ monocytes were cultured for 5 days in RPMI 10% FCS containing GM-CSF and IL-4 to generate immature monocyte-derived dendritic cells (MDDC). Immature MDDC were exposed to MEK inhibitor, U0126, or p38MAPK inhibitor, SB203580 for 1 hour and a final dose of GM-CSF and IL-4 were added to the culture. Cells were collected for analysis after 4, 10 or 24 hours.Total RNA from each condition was extracted using the All prep DNA/RNA/protein mini kit (Qiagen) and hybridized to an Agilent Human Whole Genome (4x44) Oligo Microarray. All experimental procedures were performed following manufacturer instructions.

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Inhibition of Met results in concomitant inhibition of Akt and STAT3 signaling pathways, while abrogation of negative feedback permits Erk reactivation

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