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

Sci Transl Med 8 September 2010:
Vol. 2, Issue 48, p. 48ra66
DOI: 10.1126/scitranslmed.3000630
Research Article
Nuclear Phospho-Akt Increase Predicts Synergy of PI3K Inhibition and Doxorubicin in Breast and Ovarian Cancer
Jeffrey J. Wallin*, Jane Guan, Wei Wei Prior, Kyle A. Edgar, Robert Kassees, Deepak Sampath, Marcia Belvin and Lori S. Friedman
+ Author Affiliations

Cancer Signaling, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
*To whom correspondence should be addressed. E-mail: jwallin@gene.com

Abstract
The phosphatidylinositol 3-kinase (PI3K)–Akt signaling pathway is frequently disrupted in cancer and implicated in multiple aspects of tumor growth and survival. In addition, increased activity of this pathway in cancer is associated with resistance to chemotherapeutic agents. Therefore, it has been hypothesized that PI3K inhibitors could help to overcome resistance to chemotherapies. We used preclinical cancer models to determine the effects of combining the DNA-damaging drug doxorubicin with GDC-0941, a class I PI3K inhibitor that is currently being tested in early-stage clinical trials. We found that PI3K inhibition significantly increased apoptosis and enhanced the antitumor effects of doxorubicin in a defined set of breast and ovarian cancer models. Doxorubicin treatment caused an increase in the amount of nuclear phospho-AktSer473 in cancer cells that rely on the PI3K pathway for survival. This increased phospho-AktSer473 response to doxorubicin correlates with the strength of GDC-0941’s effect to augment doxorubicin action. These studies predict that clinical use of combination therapies with GDC-0941 in addition to DNA-damaging agents will be effective in tumors that rely on the PI3K pathway for survival.

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).

Received for publication 12 November 2009. Accepted for publication 19 August 2010.
Copyright © 2010, American Association for the Advancement of Science

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