Research ArticleCancer Drug Development

Pathway-Based Identification of Biomarkers for Targeted Therapeutics: Personalized Oncology with PI3K Pathway Inhibitors

Science Translational Medicine  04 Aug 2010:
Vol. 2, Issue 43, pp. 43ra55
DOI: 10.1126/scitranslmed.3001065

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Toward Customizing Tumor Treatment

Just as our view of Earth has become increasingly global, cells are now seen as complex networks of interacting and intersecting signaling pathways rather than a collection of regulated genes. This new view applies to cancer cells as well, which we now know have entire dysregulated pathways and not just dysregulated genes. Andersen and colleagues have identified phosphoprotein biomarkers for a pathway often altered in cancer—the phosphatidylinositol 3-kinase (PI3K) pathway—and have shown that one of these predicts the sensitivity of cancer cells to a promising class of cancer drugs: inhibitors of AKT, a kinase that promotes growth and inhibits cell death.

To find useful markers of the PI3K pathway, the authors focused on a vital biochemical event—the addition of phosphate groups to serines and threonines in cellular proteins. Cells use this simple covalent modification over and over again to regulate protein-protein binding and activity of key enzymes. Measurement of this modification in specific proteins reveals their activation. The authors monitored 375 phosphorylation sites in the PI3K pathway after treating prostate cancer cells with three different PI3K pathway inhibitors, potentially useful drugs. They found that each drug modulated a specific array of phosphoproteins, with some overlap, many of them within proteins that participate in cytoskeletal remodeling, vesicle transport, and protein translation. In theory, each phosphopeptide that decreased in abundance after drug treatment could, if elevated in cancer cells, serve as a biomarker of sensitivity to that drug. To show that this was the case, the authors chose one of the phosphorylated sites (the threonine at position 246 of the cytoplasmic protein PRAS40) and generated a high-quality antibody to it. The amount of phosphorylation at Thr246 correlated with activation of the PI3K pathway in human cancer cell lines, in a mouse prostate tumor, and in triple-negative breast tumors. Of potentially even more utility, Thr246 phosphorylation predicted the sensitivity of these cells to AKT inhibitors.

Cancers are extremely heterogeneous, even within tissues, and for optimal effectiveness, treatments need to be customized accordingly. As this work shows, phosphorylated amino acids can serve as biomarkers for activated pathways in cancer and, because specific antibodies can easily be made to these phosphorylated peptides, can be readily measured. These results point to a way, after further development of more biomarkers, to routinely characterize the activated pathways in patients’ cancers. A tumor characterized in this way can then be treated with the appropriate pathway-specific drugs, optimizing the chances of eradicating the tumor.


  • * These authors contributed equally to this work.

  • Present address: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

  • Present address: Biogen Idec, Cambridge, MA 02432, USA.

  • || Present address: Daiichi Sankyo Research Institute, Daiichi Sankyo, Inc., Edison, NJ 08837, USA.

  • Citation: J. N. Andersen, S. Sathyanarayanan, A. Di Bacco, A. Chi, T. Zhang, A. H. Chen, B. Dolinski, M. Kraus, B. Roberts, W. Arthur, R. A. Klinghoffer, D. Gargano, L. Li, I. Feldman, B. Lynch, J. Rush, R. C. Hendrickson, P. Blume-Jensen, C. P. Paweletz, Pathway-based identification of biomarkers for targeted therapeutics: Personalized oncology with PI3K pathway inhibitors. Sci. Transl. Med. 2, 43ra55 (2010).