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 Mills, Shannon R. Morris, Rakesh Kumar, Hani Gabra, Euan A. Stronach

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 - Jan 1 2015
Externally publishedYes

Fingerprint

Biomarkers
Platinum
Proteomics
Ovarian Neoplasms
Biopsy
Clinical Trials, Phase I
Molecular Imaging
Deoxyglucose
GSK2141795
In Vitro Techniques
mechanistic target of rapamycin complex 1
Tumor Burden
Cisplatin
Therapeutics
Phosphorylation
Apoptosis
Growth

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

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

In: Oncotarget, Vol. 6, No. 39, 01.01.2015, p. 41736-41749.

Research output: Contribution to journalArticle

Cheraghchi-Bashi, A, Parker, CA, Curry, E, Salazar, JF, Gungor, H, Saleem, A, Cunnea, P, Rama, N, Salinas, C, Mills, G, Morris, SR, Kumar, R, Gabra, H & Stronach, EA 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, vol. 6, no. 39, pp. 41736-41749. https://doi.org/10.18632/oncotarget.6153
Cheraghchi-Bashi, Azadeh ; Parker, Christine A. ; Curry, Ed ; Salazar, Jean Frederic ; Gungor, Hatice ; Saleem, Azeem ; Cunnea, Paula ; Rama, Nona ; Salinas, Cristian ; Mills, Gordon ; Morris, Shannon R. ; Kumar, Rakesh ; Gabra, Hani ; Stronach, Euan A. / 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. In: Oncotarget. 2015 ; Vol. 6, No. 39. pp. 41736-41749.
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