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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Antibody-based profiling of the phosphoinositide 3-kinase pathway in clinical prostate cancer
George V Thomas1, Steve Horvath, Bradley L Smith
1Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California 90095, USA.
Purpose:
As kinase inhibitors transition from the laboratory to patients, it is imperative to develop biomarkers that can be used in the clinic. The primary objectives are to identify patients most likely to benefit from molecularly targeted therapies and to document modulation of the drug target. Constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway and its downstream effectors, as a result of PTEN loss or by other mechanisms, occurs in a high proportion of prostate cancers, making it an ideal template for the design of clinical trials involving PI3K pathway inhibitors. Prostate cancers also present unique organ-specific challenges, in that tumors are heterogeneous and diagnostic tissue is extremely limited.
Experimental Design:
Working within these limitations, we have developed a set of immunohistochemical assays that define activation of the PI3K pathway in clinical samples.
Results And Conclusions:
Using both univariate and multivariate analyses, we show that loss of PTEN is highly correlated with the activation of AKT, and this, in turn, is associated with the phosphorylation of S6, one of its main effectors. These three antibodies are potentially able to define a molecular signature of PTEN loss and/or AKT pathway activation in prostate cancer.
Insights
Biomarkers are crucial for targeted cancer therapies. This study developed immunohistochemical assays to detect PTEN loss and PI3K pathway activation in prostate cancer, aiding patient selection for clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Kinase inhibitors are transitioning to clinical use, necessitating reliable biomarkers.
- Prostate cancer frequently exhibits phosphoinositide 3-kinase (PI3K) pathway activation, making it a model for targeted therapy trials.
- Tumor heterogeneity and limited tissue in prostate cancer pose challenges for biomarker development.
Purpose of the Study:
- To identify patients who will benefit from molecularly targeted therapies.
- To develop clinical biomarkers for PI3K pathway inhibitors.
- To establish a molecular signature for PTEN loss and/or PI3K pathway activation in prostate cancer.
Main Methods:
- Development of immunohistochemical assays for clinical samples.
- Analysis of PTEN loss, AKT activation, and S6 phosphorylation.
- Univariate and multivariate statistical analyses.
Main Results:
- Loss of PTEN is strongly correlated with AKT activation.
- AKT activation is associated with the phosphorylation of S6.
- The developed assays can define a molecular signature of PTEN loss and PI3K pathway activation.
Conclusions:
- Immunohistochemical assays can define PI3K pathway activation in prostate cancer.
- These assays hold potential for patient stratification in clinical trials.
- A molecular signature of PTEN loss and AKT pathway activation can be established.
