Assessing the extent of phosphoinositol 3-kinase (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 to 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).
While 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 immunohistochemical score of PI3K pathway activity correlates with features of PI3K activation.
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.
Mol Cancer Res. 2015 Jun 29. pii: molcanres.0569.2014. [Epub ahead of print]
Martin NE1, Gerke T2, Sinnott JA2, Stack EC3, Andren O4, Andersson SO4, Johansson JE4, Fiorentino M5, Finn S6, Fedele G7, Stampfer M8, Kantoff PW9, Mucci LA8, Loda M10.
1 Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital
2 Department of Epidemiology, Harvard School of Public Health.
3 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School.
4 Urology, Orebro University, School of Health and Medical Sciences.
5 Pathology Unit, Addarii Institute, S Orsola-Malpighi Hospital.
6 Pathology, Trinity College.
7 Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute.
8 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School.
9 Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School.
10 Division of Cancer Studies, King's College London.