Therapeutics, Targets, and Chemical Biology Akt Kinase-Interacting Protein 1 Signals through CREB to Drive Diffuse Malignant

Diffuse malignant mesothelioma (DMM) is a tumor of serosal membranes with propensity for progressive local dis-ease. Because current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve the out-comes of patients with this disease. Akt kinase interacting protein 1 (Aki1; Freud-1/CC2D1A) is a scaffold protein for the PI3K–PDK1–Akt signaling module that helps determine receptor signal selectivity for EGFR. Aki1 has been suggested as a therapeutic target, but its potential has yet to be evaluated in a tumor setting. Here, we report evidence supporting its defini-tion as a therapeutic target in DMM. In cell-based assays, Aki1 silencing decreased cell viability and caused cell-cycle arrest of multiple DMM cell lines via effects on the PKA–CREB1 signal-ing pathway. Blocking CREB activity phenocopied Aki1 silenc-ing. Clinically, Aki1 was expressed in most human DMM specimens where its expression correlated with phosphorylated CREB1. Notably, Aki1 siRNA potently blocked tumor growth in an orthotopic implantation model of DMMwhen administered directly into the pleural cavity of tumor-bearing mice. Our findings suggest an important role for the Aki1–CREB axis in DMM pathogenesis and provide a preclinical rationale to target Aki1 by intrathoracic therapy in locally advanced tumors. Cancer Res; 75(19); 1–10. 2015 AACR