Research ArticleCancer

Nuclear Phospho-Akt Increase Predicts Synergy of PI3K Inhibition and Doxorubicin in Breast and Ovarian Cancer

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Science Translational Medicine  08 Sep 2010:
Vol. 2, Issue 48, pp. 48ra66
DOI: 10.1126/scitranslmed.3000630

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Timing the Delivery of a One-Two Punch

How to effectively target and eradicate lingering cancer cells that evade surgical, radiological, or even chemotherapeutic treatments remains one of the most confounding questions in cancer biology. Although complex mechanisms underlie the etiology and inherent heterogeneity of the disease, the manipulation of growth signaling pathways offers several avenues for efficient intervention. In many cancers, a key growth pathway—the phosphatidylinositol 3-kinase (PI3K) pathway—can be activated at one or several points, encouraging efforts to inhibit critical proteins. Yet, cancer cells are smart; they reach out and evolve new ways of resisting such setbacks, turning on new pathways or alternate effector proteins to achieve the same result: incessant growth. Now, Wallin and colleagues have taken aim at this pathway in a large panel of breast and ovarian cancer cell lines by investigating the combinatorial effects of PI3K pathway inhibitors and DNA damage inflicted with a common chemotherapeutic agent, doxorubicin. When the authors probed the basis of the cell lines’ susceptibility to growth inhibition in the presence of one or both drugs, they found that activation of a master serine-threonine kinase, Akt, by phosphorylation was higher in cancer lines that benefited from the drugs in combination, irrespective of PI3K pathway activation status or p53 mutational status. Similar experiments in mice carrying tumors recapitulated these findings and, importantly, the drug combination did not elevate Akt phosphorylation in nontumor tissues. Together, these findings suggest that the activation of Akt in tumor tissues may mark the vulnerability of a cancer to combination therapy with a PI3K inhibitor and a DNA-damaging agent. This proposal will need to be explored further in the clinic, but the utility of tandem drug treatments shown here offers hope for curbing this class of cancers.

Footnotes

  • Citation: J. J. Wallin, J. Guan, W. W. Prior, K. A. Edgar, R. Kassees, D. Sampath, M. Belvin, L. S. Friedman, Nuclear phospho-Akt increase predicts synergy of PI3K inhibition and doxorubicin in breast and ovarian cancer. Sci. Transl. Med. 2, 48ra66 (2010).