Aug. 25, 2008 Two independent research groups have found that simultaneous inhibition of two signaling pathways resulted in substantially enhanced antitumor effects in mouse models of prostate and breast cancer. In an accompany commentary, Steven Grant, at Virginia Commonwealth University Health Science Center, Richmond, discusses the clinical importance of these studies and highlights some of the questions that still need to be answered.
In the first study, Pier Paolo Pandolfi and colleagues, at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, and Memorial Sloan-Kettering Cancer Center, New York, report that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with a drug that inhibits the mTOR signaling pathway showed increased activation of the MAPK signaling pathway. Similar results were observed in a mouse model of prostate cancer following treatment with the same drug.
As inhibition of the MAPK signaling pathway enhanced the antitumoral effects of inhibition of the mTOR signaling pathway in mice transplanted with a human breast cancer cell line, the authors suggest that a combination therapy using drugs that target each pathway might improve the treatment of human cancers.
In the second study, Cory Abate-Shen and colleagues, at Columbia University College of Physicians and Surgeons, New York, and the University of Medicine & Dentistry of New Jersey, Piscataway, show that simultaneous inhibition of the mTOR and MAPK signaling pathways inhibited the in vitro growth of prostate cancer cell lines and the in vivo growth of prostate tumors in a mouse model of prostate cancer. This was particularly true in a model of highly aggressive and frequently lethal forms of the disease, which do not respond to hormone deprivation therapy, leading the authors to suggest that this combination therapy might be particularly useful for treating patients with advanced, hormone-refractory prostate cancer.
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- Carracedo et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. Journal of Clinical Investigation, 2008; DOI: 10.1172/JCI34739
- Kinkade et al. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. Journal of Clinical Investigation, 2008; DOI: 10.1172/JCI34764
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