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

Abstract

Purpose: 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 AKTdependent therapeutic responses, remains unclear.Experimental Design: 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. In vitro assays, in vivo 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.Results: 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 in vivo. AKT allosteric inhibitors were shown to only block the growth of Trop-2-expressing tumor cells, both in vitro and in preclinical models, being ineffective on Trop-2-null cells. Consistently, AKTtargeted 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.Conclusions: 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. Clin Cancer Res; 22(16); 4197-205. Ó2016 AACR.

Distinct lung cancer subtypes associate to distinct drivers of tumor progression

“…Notably, though, our findings indicated that TROP2 has a vast negative prognostic impact on LUAD, but only a marginal one on LUSC, where Trop-2 expression associates to terminal differentiation to cornified cells [ 11 ], with formation of keratin pearls (Figure 1A ). Parallel findings were obtained for TP63 , which we had previously shown to be both an upstream driver of Trop-2 [ 8 , 9 ] and a downstream effector [ 12 ]. TP63 is a powerful diagnostic discriminant [ 13 ], and a cancer prognostic [ 14 ] and predictive [ 15 ] factor.…”

Trop2: Jack of All Trades, Master of None

“…By contrast, numerous studies reported activation of Akt kinase by Trop2, mostly in cancer cell lines [ 54 , 55 , 56 , 57 , 58 ] but also in murine mesenchymal stem cells [ 26 ]. A large proteomic analysis recently identified more than 100 signaling molecules modulated by Trop2, with PTEN/PIK3CA/Akt/GSK3ß being a major activated pathway in cancer cells [ 59 ].…”

“…Despite the fact that Trop2 is considered a transmembrane protein, it can also be localized in the cytoplasm with possible functional consequences [ 42 , 65 , 76 ]. Cytoplasmic, but not membrane-bound Trop2, expression positively correlates with phospho-Akt in breast cancer specimens [ 59 ]. Stoyanova et al reported that Trop2 undergoes regulated intramembrane proteolysis (RIP) [ 67 ].…”

“…As expected, modulation of Trop2 signaling through the epidermal growth factor receptor 3 (ErbB3), insulin-like growth factor 1 receptor (IGF-1R), and Akt pathways (see Chapter 2.2 and 3.2.6) reflects the observed association between Trop2 expression and resistance to EGFR inhibitor gefinitib in head-and-neck squamous cell carcinoma [ 148 ], altered response of Trop2-overexpressing cells to IGF-1R inhibitor AG-1024 in HeLa cells [ 77 ], and reduced response of Trop2 shRNA transfected breast cancer cells to allosteric Akt inhibitors [ 59 ].…”

<p>Plausibility of trophoblastic-like regulation of cancer tissue</p>

“…It induces intracellular calcium release and activates the MAPK and Akt signaling pathways, thus implementing cell growth and EMT. 66,67 Its anti-adhesive activity boosts the migratory phenotype. 68 Trop-2 is a marker of cell stemness and is present in many normal tissues.…”