title: Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Guerra
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Trerotola
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Tripaldi
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Anna Laura
authors.initials: AL
authors.lastname: Aloisi
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Simeone
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sacchetti
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Relli
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Amore
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: La Sorda
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy. Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Rossano
authors.initials: R
authors.lastname: Lattanzio
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy. Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio,' Chieti, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Piantelli
authors.affiliation: Unit of Cancer Pathology, CeSI-MeT, University 'G. d'Annunzio,' Chieti, Italy. Department of Neuroscience, Imaging and Clinical Sciences, Unit of Physiology and Physiopathology, University 'G. d'Annunzio,' Chieti, Italy. s.alberti@unich.it.
authors.forename: Saverio
authors.initials: S
authors.lastname: Alberti
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D047428:Protein Kinase Inhibitors; C499380:TACSTD2 protein, human; D051057:Proto-Oncogene Proteins c-akt