Neratinib decreases pro-survival responses of [sorafenib + vorinostat] in pancreatic cancer

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.

Keywords: Autophagy; Endoplasmic reticulum (ER) stress; HDAC inhibitor; Neratinib; Sorafenib; Vorinostat.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.