Abstract
BackgroundSignaling networks promoting cell growth and proliferation are frequently deregulated in cancer. Tumors often are highly dependent on such signaling pathways and may become hypersensitive to downregulation of key components within these signaling cascades. The classical mitogenic cascade transmits stimuli from growth factor receptors via Ras, Raf, MEK and ERK to the cell nucleus and provides attractive molecular targets for cancer treatment. For example, Ras and Raf kinase inhibitors are already in a number of ongoing phase II and phase III clinical trials. In this study the effect of the Raf kinase inhibitor BAY 43-9006 and of the MEK inhibitor CI-1040 (PD184352) on a Raf dependent lung tumor mouse model was analyzed in detail.MethodsWe have generated a lung cancer mouse model by targeting constitutively active C-Raf kinase to the lung. These mice develop adenomas within 4 months of life. At this time-point they received daily intraperitoneal injections of either 100 mg/kg BAY 43-9006 or CI-1040 for additional 21 days. Thereafter, lungs were isolated and the following parameters were analyzed using histology and immunohistochemistry: overall lung structure, frequency of adenoma foci, proliferation rate, ERK activity, caspase-3 activation, and lung differentiation.ResultsBoth inhibitors were equally effective in vitro using a sensitive Raf/MEK/ERK ELISA. In vivo, the systemic administration of the MEK inhibitor CI-1040 reduced adenoma formation to a third and significantly restored lung structure. The proliferation rate of lung cells of mice treated with CL-1040 was decreased without any obvious effects on differentiation of pneumocytes. In contrast, the Raf inhibitor BAY 43-9006 did not influence adenoma formation in vivo.ConclusionThe MEK inhibitor CI-1040 may be used for the treatment of Ras and/or Raf-dependent human malignancies.
Highlights
Signaling networks promoting cell growth and proliferation are frequently deregulated in cancer
Oncogene-based therapeutics is a novel approach to inhibit proteins, which are essential for the initiation and maintenance of malignancies [1]
MAP kinase pathway has a central role in regulating tumor cell growth and survival, differentiation and angiogenesis and has been targeted for therapeutic intervention in the past [3,4]
Summary
Signaling networks promoting cell growth and proliferation are frequently deregulated in cancer. The classical mitogenic cascade transmits stimuli from growth factor receptors via Ras, Raf, MEK and ERK to the cell nucleus and provides attractive molecular targets for cancer treatment. Oncogene-based therapeutics is a novel approach to inhibit proteins, which are essential for the initiation and maintenance of malignancies [1]. Agents such as Herceptin for the treatment of advanced breast cancer and Gleevec for chronic myelogenous leukemia have proven that cancer therapies targeting specific molecular alterations in signaling pathways are successful [2]. C-Raf kinase and MEK are downstream effectors of the Ras signaling cascade Both kinases are essential for cellular homeostasis and induce both proliferation and survival by suppression of apoptosis [5]. Raf and Ras mutations found in human malignancies convey constitutive activity to these signaling molecules thereby converting them into an oncogenic state [6]
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