A novel therapeutic opportunity for the most aggressive sub‐type of pancreatic cancer: Targeting keratin 17 dependency on nuclear export

Abstract

Introduction and hypothesesThe purpose of this study was to uncover a novel targeted therapeutic approach for pancreatic ductal adenocarcinoma (PDAC). We previously discovered that keratin 17 (K17) is an independent negative prognostic biomarker for PDAC, where high K17 expression is associated with decreased patient survival. In our pre‐clinical mouse model, PDACs that overexpress K17 were four times more likely than controls to result in fatality within 7 weeks, suggesting that K17 drives tumor aggression. We determined that K17 functions as an oncoprotein by translocating into the nucleus of PDAC cells and enhances XPO‐1‐ mediated nuclear export and degradation of tumor suppressor proteins (TSPs).Here, we hypothesized that 1) K17 depends on nuclear export to drive tumor aggression and is highly sensitive to nuclear inhibition, compared to K17‐negative PDACs, and 2) blocking K17 enhanced XPO‐1‐mediated nuclear export causes enhanced apoptosis and cell cycle arrest.Methods and resultsTo test the hypothesis that K17 depends on nuclear export to drive tumor aggression and is more sensitive to nuclear inhibition than K17‐negative PDACs, we performed pre‐clinical studies in mouse models and orthotopically implanted isogenic murine PDAC cells (LSL‐KrasG12D, LSL‐Trp53R172HPdx‐1‐Cre, KPC) that expressed human K17 (KPC‐K17) or not (KPC‐EV) in immunocompetent animals. After animal randomization, mice were treated three times weekly via oral gavage with selinexor, an inhibitor of the nuclear exporter, XPO‐1, that is currently in phase 2 clinical trials. We found that selinexor inhibited the growth of K17‐positive PDACs in mice, compared to K17‐negative PDACs, suggesting that K17sensitizes PDACs to selinexor treatment. To determine if this decreased tumor growth was due to a tumor‐cell nuclear export blockage, we performed in vitro studies and found that KPC‐K17 cells elicited a four‐fold increase in cell death and a two‐fold increase in G1/S cell cycle arrest compared to KPC‐EV cells. In addition, selinexor treatment led to nuclear retention of K17. To test the dependency of KPC‐K17 cells to K17‐mediated nuclear export, we challenged the cells to chemotherapeutic and targeted therapeutic agents that induce nuclear import inhibition (ivermectin), G1/S transition inhibition (palbociclib), and DNA‐damage (oxaliplatin). In contrast to selinexor treatment, there were no differences in cell death or cell cycle arrest between KPC‐K17 and KPC‐EV cells upon treatment with these compounds.ConclusionsOur results suggest that K17‐positive tumors are specifically vulnerable to inhibition of nuclear export. Given that K17 expression is a biomarker that drives tumor aggression in PDACs, our results suggest that treatment with selinexor is a novel therapeutic opportunity for the most aggressive sub‐type of pancreatic cancer.Support or Funding InformationPancreatic Cancer Action Network