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| |  Combination of MEK and PI3K Inhibitors Induces Cell Cycle Arrest, While Dual Inhibition of PI3K and mTOR Induces Apoptosis in Breast Cancer Cells: Presented at AACR-NCI-EORTC By Crina Frincu-Mallos, PhD SAN FRANCISCO, CA -- October 30, 2007 -- Targeted inhibition of two pathways involved in controlling cell growth -- the MEK pathway and the PI3K pathway -- resulted in uncovering two targets that, when chemically blocked at the same time, resulted in programmed cell death (apoptosis) in breast cancer cells, researchers reported here at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. "The chemical networks involved in cell cycle control have a tendency to be much more complicated than we initially expect, with intersecting pathways and feedback loops," said W. Michael Korn, MD, Associate Professor, University of California, San Francisco, (UCSF) Comprehensive Cancer Center, San Francisco, California, United States. "To understand the connections between these pathways we have taken a systems biology approach, one that may uncover new anticancer drug targets on different levels within connecting pathways," Dr. Korn said. The lead author of the study, Olga K. Mirzoeva, PhD, and other researchers at UCSF, Lawrence Berkeley National Laboratories, and The University of Texas M. D. Anderson Cancer Center are creating computer models aimed at identifying key proteins within the signalling networks. "There are so many different components involved that modelling these pathways is as complicated as creating computer models that accurately predict the weather," Dr. Korn said. In analysing the performance of the MEK inhibitors, the researchers noticed that a similar pathway, identified by the activity of an enzyme called PI3-kinase, had been activated. "So, of course, we decided that we would try blocking the PI3-kinase pathway as well, assuming that simply blocking both pathways would work," Dr. Korn said. However, combining the different inhibitors (ie, MEK inhibitors and a PI3-kinase inhibitor) resulted in an unpredicted antiapoptotic effect. These compounds induced G1 arrest in asynchronous cell cultures of breast cancer cells, said Dr. Mirzoeva. In addition, reverse phase protein lysate array analysis indicated the activation of PI3-kinase signalling. "That is when we decided to look elsewhere along the MEK and PI3-kinase pathways, eventually trying MEK inhibitors in combination with a number of inhibitors along the PI3-kinase pathway," Dr. Korn said. Using MDAMB231 cell lines, Dr. Mirzoeva and colleagues performed an analysis of the effect of combining specific the small-molecule MEK inhibitors CI1040 and U0126, with PIK90, a specific inhibitor of the p110-alpha subunit and PI103a dual inhibitor of PI3-kinase and mTOR. The number of viable cells was determined at 72 hours post-drug treatment, using ATP-based cell-titer assay. To assess the effect of using the inhibitors in various combinations, Dr. Mirzoeva and colleagues looked at the combination index (CI<1 indicates synergistic effect). The following combinations showed synergistic effect in the MDAMB231 cell lines: PIK90 + CI1040 (CI=.286), PI103 + CI1040 (CI=.729), PIK90 + U0126 (CI=.62), and PI103 + U0126 (CI=.916). In conclusion, by combining pharmacological inhibitors of MEK with specific inhibitors of PI3K-p110a, synergistic growth inhibition was seen in breast cancer cells, by induction of cell cycle arrest, but not apoptosis, explained Dr. Mirzoeva. The researchers found that targeting PI3-kinase in conjunction with TOR, a protein farther down the pathway, pushed breast cancer cells dramatically into apoptosis. Interestingly, dual inhibition of PI3K-p110a and mTOR had synergistic proapoptotic effects, noted the researchers. Rapamycin, an immunosuppressant known as a TOR inhibitor, is currently studied in combination with a PI3-kinase inhibitor in additional breast cancer cell lines. Depending on the preclinical results, the combination might go into clinical trials, according to the researchers. Funding for this study was provided by the Integrative Cancer Biology Program, National Cancer Institute, United States National Institutes of Health.
[Presentation title: Synergistic effects of multi-level targeting of the MAPK and PI3-kinase pathways in breast cancer cells. Abstract B128]
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