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

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 eIF2 alpha and NF kappa B and the expression of Beclin1, ATG5 and CD95; and suppressed the levels of beta-catenin. Knock down of Beclin1, ATG5, CD95, eIF2 alpha or NF kappa B suppressed cell killing whereas knock down of beta-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 NF kappa B 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.