Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Meningiomas (MN) arise from the arachnoid/meningeal layer and are non-responsive to chemotherapies, with ~50-60% showing loss of the Neurofibromatosis 2 (NF2) tumor suppressor gene. Previously we established NF2 loss activates mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 signaling, leading to clinical trials for NF2 and meningioma. Recently our 'omics studies identified activated ephrin (EPH) receptor and Src family kinases upon NF2 loss. Here, we report increased expression of several ligands in both NF2-null human arachnoidal cells (ACs) and the MN cell line Ben-Men-1, particularly NRG1/neuregulin 1, and confirm increased NRG1 secretion and activation of ERBB3 receptor tyrosine kinase to which NRG1 binds. Conditioned-medium from NF2-null ACs or exogenous NRG1 stimulated ERBB3, EPHA2 and mTORC1/2 signaling, suggesting pathway crosstalk. NF2-null cells treated with an ERBB3-neutralizing antibody partially downregulated basal mTOR pathway activation but showed no effect on viability. mTORC1/2 inhibitor treatment decreased NRG1 expression and downregulated ERBB3 while re-activating pAkt T308, suggesting a PDK1-dependent signaling mechanism independent of NRG1-ERBB3, but likely involving activation of another upstream receptor kinase. Transcriptomics after mTORC1/2 inhibition confirmed decreased ERBB3/ERBB4 while revealing increased expression of another receptor tyrosine kinase, IGF1R Drug treatment co-targeting mTORC1/2 and IGF1R/IR in NF2-null cells attenuated pAkt T308 and showed synergistic effects on viability. Our findings indicate potential autocrine signaling where NF2 loss leads to secretion of NRG1 and activation of ERBB3. mTORC1/2 inhibition downregulates NRG1-ERBB3, while upregulating pAkt T308 through an adaptive response involving IGF1R/IR, suggesting that co-targeting these pathways may prove effective for treatment of NF2-deficient meningioma.
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PMID:mTOR kinase inhibition disrupts neuregulin 1-ERBB3 autocrine signaling and sensitizes NF2-deficient meningioma cellular models to IGF1R inhibition. 3327 14