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

Azadeh Cheraghchi-Bashi, Christine A. Parker, Ed Curry, Jean Frederic Salazar, Hatice Gungor, Azeem Saleem, Paula Cunnea, Nona Rama, Cristian Salinas, Gordon B. Mills, Shannon R. Morris, Rakesh Kumar, Hani Gabra, Euan A. Stronach

    Research output: Contribution to journalArticle

    14 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)41736-41749
    Number of pages14
    JournalOncotarget
    Volume6
    Issue number39
    DOIs
    StatePublished - 2015

    Keywords

    • AKT
    • Biomarkers
    • Ovarian cancer
    • Platinum resistance
    • Proteomics

    ASJC Scopus subject areas

    • Oncology

    Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Cheraghchi-Bashi, A., Parker, C. A., Curry, E., Salazar, J. F., Gungor, H., Saleem, A., Cunnea, P., Rama, N., Salinas, C., Mills, G. B., Morris, S. R., Kumar, R., Gabra, H., & Stronach, E. A. (2015). 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. Oncotarget, 6(39), 41736-41749. https://doi.org/10.18632/oncotarget.6153