Evaluation and Clinical Analyses of Downstream Targets of the Akt Inhibitor GDC-0068

The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3...

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Published in:Clinical cancer research 2013-12, Vol.19 (24), p.6976-6986
Main Authors: YIBING YAN, SERRA, Violeta, WAGLE, Marie-Claire, WU, Jenny Q, WONGCHENKO, Matthew, HAMPTON, Garret, RAMAKRISHNAN, Vanitha, LACKNER, Mark R, SAURA, Cristina, RODA, Desamparados, CERVANTES, Andrés, TABERNERO, Josep, PRUDKIN, Ludmila, PATEL, Premal, BASELGA, José, SCALTRITI, Maurizio, MURLI, Sumati, RODRIGUEZ, Olga, GUZMAN, Marta, SAMPATH, Deepak, NANNINI, Michelle, YUANYUAN XIAO
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Humans
Medical sciences
Mice
Oncogene Protein v-akt - antagonists & inhibitors
Oncogene Protein v-akt - genetics
Pharmacology. Drug treatments
Phosphatidylinositol 3-Kinases - metabolism
Piperazines - administration & dosage
Protein Kinase Inhibitors - administration & dosage
Pyrimidines - administration & dosage
Pyrimidines - pharmacology
Signal Transduction - genetics
TOR Serine-Threonine Kinases - genetics
TOR Serine-Threonine Kinases - metabolism
Xenograft Model Antitumor Assays
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Summary:The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound. We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker set in pre- and post-dose tumor biopsies from patients treated with GDC-0068 in the dose escalation clinical trial. The set of biomarkers of Akt inhibition is composed of 10 phosphoproteins, including Akt and PRAS40, and is modulated in a dose-dependent fashion, both in vitro and in vivo. In human-tumor xenografts, this dose dependency significantly correlated with tumor growth inhibition. Tumor biopsies from patients treated with GDC-0068 at clinically achievable doses attained a degree of biomarker inhibition that correlated with tumor growth inhibition in preclinical models. In these clinical samples, compensatory feedback activation of ERK and HER3 was observed, consistent with preclinical observations. This study identified a set of biomarkers of Akt inhibition that can be used in the clinical setting to assess target engagement. Here, it was used to show that robust Akt inhibition in tumors from patients treated with GDC-0068 is achievable, supporting the clinical development of this compound in defined patient populations.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-13-0978