Annexin A8 Drives MEK Inhibitor Resistance, Providing a Druggable Target for Pancreatic Ductal Adenocarcinoma

Mitogen-activated protein kinase kinase (MEK) is a component of an important signaling pathway involved in the development and progression of pancreatic ductal adenocarcinoma (PDAC). However, MEK-targeted therapeutics are not effective, and therefore not indicated, for patients with PDAC. We have found that annexin A8 (ANXA8) is involved in resistance to MEK inhibitor therapy in PDAC. Expression of ANXA8 was induced at both the mRNA and protein levels early by MEK inhibitor treatment in PDAC cells, and the level of ANXA8 mRNA expression was inversely correlated with sensitivity to the MEK inhibitor. Furthermore, downregulation of ANXA8 enhanced the inhibitory effect of the MEK inhibitor on PDAC cell proliferation, suggesting that ANXA8 could be a potential therapeutic target for PDAC. To achieve a therapeutic strategy targeting ANXA8, we have identified all-trans retinoic acid (ATRA) as a compound exerting ANXA8-inhibitory effects in PDAC cells. Combination of the MEK inhibitor and ATRA demonstrated additive antitumor effects in PDAC cells in vitro and in vivo. IHC analysis revealed that ANXA8 was frequently upregulated in PDAC showing poor differentiation relative to PDAC with high or moderate differentiation. Furthermore, patients with ANXA8-positive PDAC were found to have a significantly poorer prognosis than those with ANXA8-negative PDAC. In summary, our findings suggest that ANXA8 plays a role in MEK inhibitor resistance in PDAC and that a combination of MEK inhibition with ANXA8-targeted therapy could be a novel effective strategy for PDAC.