Novel Approaches for Molecular Targeted Therapy of Breast Cancer: Interfering with PI3K/AKT/mTOR Signaling
Thomas W. Grunt,
Gabriella L. Mariani.
Breast cancer is one of the most prevalent and devastating malignant diseases in women worldwide.
Fortunately, while breast cancer incidence is still increasing, its death rate is declining. This is mainly due to early
diagnosis and potent therapies such as blockade of estrogen receptor- or of ErbB2 (HER2-neu) membrane receptorsignaling.
In recent years, the PI3K/AKT/mTOR pathway, which transmits signals from the cell membrane into the
nucleus and activates multiple oncogenic programs, has been found to play a crucial role in the regulation of breast cancer
cell growth. This pathway is densely interconnected with a multitude of other important regulatory systems for glucose-,
lipid- and amino acid-metabolism, for energy balance, and for autophagy. It has been found that PI3K/AKT/mTOR
signaling modulates estrogen receptor function. Using transverse and feedback regulatory loops the PI3K/AKT/mTOR
cascade can communicate with concurrent and with upstream systems. Thus, PI3K/AKT/mTOR is a crucial element
within a complicated signaling network. This pathway is hyperactive in more than 70% of breast tumors. Hence, the
protein kinases located along this route represent very attractive and promising drug targets for breast cancer therapy.
Currently, numerous small molecular drugs that inhibit PI3K, AKT and/or mTOR are being developed in preclinical and
clinical models of breast cancer. Some of these compounds are highly selective blocking only one particular kinase
complex, whereas others interfere with two (mTORC1+mTORC2) or even three effectors (PI3K+mTORC1+mTORC2) of
the pathway. Due to the many interactions with other regulatory systems, silencing of the pathway can cause unexpected
results. Therefore, detailed preclinical and clinical evaluation of these compounds as single drugs and in combination is
required to achieve optimal results with maximal clinical benefit and acceptable toxicity. Also, reliable biomarkers for the
identification of patient subsets that will maximally benefit from PI3K/AKT/mTOR inhibition need to be developed.
Thus, selective silencing of PI3K/AKT/mTOR signaling represents a promising approach for breast cancer and might
prove useful when combined with other drugs. Here we review the current preclinical and clinical data and compare the
potential benefits of multi- versus single-targeting PI3K/AKT/mTOR drugs.
Keywords: AKT, breast cancer, drug targeting, inhibitor, mTOR, PI3K, receptor tyrosine kinase, signal transduction.
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