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Mol Cancer Res. 2015 Oct;13(10):1431-40. doi: 10.1158/1541-7786.MCR-14-0569. Epub 2015 Jun 29.

Measuring PI3K Activation: Clinicopathologic, Immunohistochemical, and RNA Expression Analysis in Prostate Cancer.

Author information

1
Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. nmartin@LROC.harvard.edu.
2
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
3
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
4
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
5
School of Health and Medical Sciences, Örebro University; and Department of Urology, Örebro University Hospital, Örebro, Sweden.
6
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. Pathology Unit, Addarii Institute, S Orsola-Malpighi Hospital, Bologna, Italy.
7
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Trinity College, Dublin, Ireland.
8
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
10
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Division of Cancer Studies, King's College London, London, United Kingdom.

Abstract

Assessing the extent of PI3K pathway activity in cancer is vital to predicting sensitivity to PI3K-targeting drugs, but the best biomarker of PI3K pathway activity in archival tumor specimens is unclear. Here, PI3K pathway activation was assessed, in clinical tissue from 1,021 men with prostate cancers, using multiple pathway nodes that include PTEN, phosphorylated AKT (pAKT), phosphorylated ribosomal protein S6 (pS6), and stathmin. Based on these markers, a 9-point score of PI3K activation was created using the combined intensity of the 4-markers and analyzed its association with proliferation (Ki67), apoptosis (TUNEL), and androgen receptor (AR) status, as well as pathologic features and cancer-specific outcomes. In addition, the PI3K activation score was compared with mRNA expression profiling data for a large subset of men. Interestingly, those tumors with higher PI3K activation scores also had higher Gleason grade (P = 0.006), increased AR (r = 0.37; P < 0.001) and Ki67 (r = 0.24; P < 0.001), and decreased TUNEL (r = -0.12; P = 0.003). Although the PI3K activation score was not associated with an increased risk of lethal outcome, a significant interaction between lethal outcome, Gleason and high PI3K score (P = 0.03) was observed. Finally, enrichment of PI3K-specific pathways was found in the mRNA expression patterns differentiating the low and high PI3K activation scores; thus, the 4-marker IHC score of PI3K pathway activity correlates with features of PI3K activation.

IMPLICATIONS:

The relationship of this activation score to sensitivity to anti-PI3K agents remains to be tested but may provide more precision guidance when selecting patients for these therapies.

PMID:
26124442
PMCID:
PMC4618038
DOI:
10.1158/1541-7786.MCR-14-0569
[Indexed for MEDLINE]
Free PMC Article

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