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
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Azadeh Cheraghchi-Bashi1,2, Christine A. Parker2,3,*, Ed Curry1,*, Jean-Frederic Salazar2, Hatice Gungor4, Azeem Saleem2,4, Paula Cunnea1, Nona Rama4, Cristian Salinas2, Gordon B. Mills5, Shannon R. Morris6, Rakesh Kumar7, Hani Gabra1,** and Euan A. Stronach1,**
1 Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK
2 GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK
3 Division of Experimental Medicine, Centre for Neuroscience, Imperial College, London, UK
4 Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, UK
5 The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6 GlaxoSmithKline, Oncology R&D, Research Triangle Park, NC, USA
7 GlaxoSmithKline, Oncology R&D, Collegeville, PA, USA
* These authors have contributed equally to this work
** Co-senior authors
Euan A. Stronach, email:
Keywords: ovarian cancer, platinum resistance, biomarkers, proteomics, AKT
Received: July 07, 2015 Accepted: September 30, 2015 Published: October 19, 2015
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.
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