Data from Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Abstract

<div>Abstract<p><b>Purpose:</b> Inhibition of AKT is a key target area for personalized cancer medicine. However, predictive markers of response to AKT inhibitors are lacking. Correspondingly, the AKT-dependent chain of command for tumor growth, which will mediate AKT-dependent therapeutic responses, remains unclear.</p><p><b>Experimental Design:</b> Proteomic profiling was utilized to identify nodal hubs of the Trop-2 cancer growth–driving network. Kinase-specific inhibitors were used to dissect Trop-2–dependent from Trop-2–independent pathways. <i>In vitro</i> assays, <i>in vivo</i> preclinical models, and case series of primary human breast cancers were utilized to define the mechanisms of Trop-2–driven growth and the mode of action of Trop-2–predicted AKT inhibitors.</p><p><b>Results:</b> Trop-2 and AKT expression was shown to be tightly coordinated in human breast cancers, with virtual overlap with AKT activation profiles at T308 and S473, consistent with functional interaction <i>in vivo</i>. AKT allosteric inhibitors were shown to only block the growth of Trop-2–expressing tumor cells, both <i>in vitro</i> and in preclinical models, being ineffective on Trop-2–null cells. Consistently, AKT-targeted siRNA only impacted on Trop-2–expressing cells. Lentiviral downregulation of endogenous Trop-2 abolished tumor response to AKT blockade, indicating Trop-2 as a mandatory activator of AKT.</p><p><b>Conclusions:</b> Our findings indicate that the expression of Trop-2 is a stringent predictor of tumor response to AKT inhibitors. They also support the identification of target-activatory pathways, as efficient predictors of response in precision cancer therapy. <i>Clin Cancer Res; 22(16); 4197–205. ©2016 AACR</i>.</p></div>