A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway.
Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK.|GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK.
Azadeh
A
Cheraghchi-Bashi
GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK.|Division of Experimental Medicine, Centre for Neuroscience, Imperial College, London, UK.
Christine A
CA
Parker
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK.
Ed
E
Curry
GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK.
Jean-Frederic
JF
Salazar
Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, UK.
Hatice
H
Gungor
GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK.|Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, UK.
Azeem
A
Saleem
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK.
Paula
P
Cunnea
Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, UK.
Nona
N
Rama
GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK.
Cristian
C
Salinas
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Gordon B
GB
Mills
GlaxoSmithKline, Oncology R&D, Research Triangle Park, NC, USA.
Shannon R
SR
Morris
GlaxoSmithKline, Oncology R&D, Collegeville, PA, USA.
Rakesh
R
Kumar
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK.
Hani
H
Gabra
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK.
Euan A
EA
Stronach
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001706:Biopsy; D018394:CA-125 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D003959:Diamines / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D040901:Proteomics / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D003959:Diamines; C000595149:GSK2141795; C451759:MUC16 protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin
AKT; biomarkers; ovarian cancer; platinum resistance; proteomics