Abstract:
:The combination of the multi-kinase and chaperone inhibitor sorafenib and the histone deacetylase inhibitor vorinostat in pancreatic cancer patients has proven to be a safe and efficacious modality (NCT02349867). We determined the evolutionary mechanisms by with pancreatic tumors become resistant to [sorafenib + vorinostat] and developed a new three-drug therapy to circumvent the resistant phenotype. Pancreatic tumors previously exposed to [sorafenib + vorinostat] evolved to activate the receptors ERBB1, ERBB2, ERBB3, c-MET and the intracellular kinase AKT. The irreversible ERBB receptor family and MAP4K inhibitor neratinib significantly enhanced the anti-tumor efficacy of [sorafenib + vorinostat]. We then determined the mechanisms by which neratinib enhanced the efficacy of [sorafenib + vorinostat]. Compared to [sorafenib + vorinostat] or to neratinib alone, the three-drug combination further enhanced the phosphorylation of eIF2α and NFκB and the expression of Beclin1, ATG5 and CD95; and suppressed the levels of β-catenin. Knock down of Beclin1, ATG5, CD95, eIF2 α or NFκB suppressed cell killing whereas knock down of β-catenin enhanced killing. The drugs interacted to increase autophagosome formation; and autophagy and cell killing were suppressed by expression of activated mTOR. A portion of the killing mechanism required CD95 signaling and knock down of NFκB prevented the drugs from increasing CD95 expression. We conclude that neratinib, by down-regulation of evolutionary activated growth factor receptors, may represent a novel follow-on clinical concept after the completion of NCT02349867.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Booth L,Poklepovic A,Dent Pdoi
10.1016/j.bcp.2020.114067subject
Has Abstractpub_date
2020-08-01 00:00:00pages
114067eissn
0006-2952issn
1873-2968pii
S0006-2952(20)30301-4journal_volume
178pub_type
临床试验,杂志文章abstract::Involvement of phosphodiesterase isoenzymes (PDEs) in guanosine-3',5'-cyclic monophosphate (cGMP) hydrolysis was analyzed in aortic smooth muscle cells. Four families of PDEs were separated from pig aorta: PDE1 (calcium-calmodulin-activated), PDE3 (cGMP-inhibited), PDE4 (adenosine 3',5'-cyclic monophosphate [cAMP]-spe...
journal_title:Biochemical pharmacology
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journal_title:Biochemical pharmacology
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
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journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
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