American Association for Cancer Research
10780432ccr151701-sup-152756_1_supp_0_3330b1.doc (137.5 kB)

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

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journal contribution
posted on 2023-03-31, 18:09 authored by Emanuela Guerra, Marco Trerotola, Romina Tripaldi, Anna Laura Aloisi, Pasquale Simeone, Andrea Sacchetti, Valeria Relli, Antonella D'Amore, Rossana La Sorda, Rossano Lattanzio, Mauro Piantelli, Saverio Alberti

Supplementary Methods: Protein microarrays,Multiplex Western blotting,Confocal time-lapse microscopy, Western blotting, Immunohistochemistry, 3D structure analysis; Supplementary Table 3:Breast cancer case series clinical and pathological parameters; the file also contains legends for Supplementary Figures 1-6.


Cassa di Risparmio della Provincia di Chieti

Compagnia di San Paolo

Italian Ministry of Health



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 AKT-dependent 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, 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.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. ©2016 AACR.

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