This article is part of the Research Topic Latest Developments in Safety Pharmacology

Review ARTICLE

Front. Pharmacol., 27 June 2012 | http://dx.doi.org/10.3389/fphar.2012.00113

Cancer therapy targeting the HER2-PI3K pathway: potential impact on the heart

Giannoula L. Klement1,3, David Goukassian2, Lynn Hlatky1, Joseph Carrozza2, James P. Morgan2 and Xinhua Yan2*
  • 1 Center of Cancer Systems Biology, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA, USA
  • 2 Cardiovascular Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA, USA
  • 3 Floating Hospital for Children at Tufts Medical Center, Boston, MA, USA

The HER2-PI3K pathway is the one of the most mutated pathways in cancer. Several drugs targeting the major kinases of this pathway have been approved by the Food and Drug Administration and many are being tested in clinical trials for the treatment of various cancers. However, the HER2-PI3K pathway is also pivotal for maintaining the physiological function of the heart, especially in the presence of cardiac stress. Clinical studies have shown that in patients treated with doxorubicin concurrently with Trastuzumab, a monoclonal antibody that blocks the HER2 receptor, the New York Heart Association class III/IV heart failure was significantly increased compared to those who were treated with doxorubicin alone (16 vs. 3%). Studies in transgenic mice have also shown that other key kinases of this pathway, such as PI3Kα, PDK1, Akt, and mTOR, are important for protecting the heart from ischemia-reperfusion and aortic stenosis induced cardiac dysfunction. Studies, however, have also shown that inhibition of PI3Kγ improve cardiac function of a failing heart. In addition, results from transgenic mouse models are not always consistent with the outcome of the pharmacological inhibition of this pathway. Here, we will review these findings and discuss how we can address the cardiac side-effects caused by inhibition of this important pathway in both cancer and cardiac biology.

Keywords: cardiotoxicity, cancer, HER2, PI3K, Akt, mTOR

Citation: Klement GL, Goukassian D, Hlatky L, Carrozza J, Morgan JP and Yan X (2012) Cancer therapy targeting the HER2-PI3K pathway: potential impact on the heart. Front. Pharmacol. 3:113. doi: 10.3389/fphar.2012.00113

Received: 30 April 2012; Accepted: 24 May 2012;
Published online: 27 June 2012.

Edited by:

Jufeng Wang, Waylandgreen, USA

Reviewed by:

Domenico Criscuolo, Genovax, Italy
Sreedharan Nair Sabarinath, Food and Drug Administration, USA

Copyright: © 2012 Klement, Goukassian, Hlatky, Carrozza, Morgan and Yan. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

*Correspondence: Xinhua Yan, Cardiovascular Medicine, Steward St. Elizabeth Medical Center, Tufts University School of Medicine, 736 Cambridge Street CBR 345, Boston, MA 02135, USA. e-mail: xinhua.yan@tufts.edu