Role of Raf Kinase in Cancer: Therapeutic Potential of Targeting the Raf/MEK/ERK Signal Transduction Pathway
Section snippets
Raf Kinase Isoforms: Gatekeepers to the Raf/MEK/ERK Signaling Pathway
The ubiquitous Raf/MEK/ERK pathway is activated by the binding of growth factors, such as transforming growth factor-alpha (TGF-α), epidermal growth factor (EGF), VEGF, and PDGF-β to their cognate receptors (eg, EGFR, VEGFR-2/-3, and PDGFR-β).19, 20, 21, 22, 23 This results in autophosphorylation by RTKs and activation of a kinase cascade that relays growth factor signals from the cell surface to the nucleus.19, 20, 21, 22, 23 As pivotal members of the Raf/MEK/ERK signaling pathway, the Raf
Oncogenic raf-1 Mutations and Malignant Transformation In Vitro
Activated oncogenic forms of raf-1 (eg, v-raf), mutant Raf proteins, and Raf-1 fusion proteins all induce transformation of cell lines in vitro. Raf-1 has been shown to mediate transformation via the MEK/ERK mitogenic pathway, and also by a MEK/ERK-independent route.44 Despite the ease with which oncogenic raf-1 mutants transform cells in vitro, tumor-specific oncogenic raf-1 mutations have been observed only rarely in human tumor-derived cell lines.45, 46 Genetic rearrangements at the Raf-1
Raf Isoforms and Tumor Progression
Dysregulated overexpression of Raf isoforms is also associated with tumor progression. Raf isoforms are involved as downstream effectors of angiogenesis, which is essential for the establishment of the necessary vasculature to facilitate solid tumor growth beyond 2 to 3 mm3. Furthermore, Raf overexpression has been associated with a more aggressive and invasive tumor phenotype and has, therefore, been implicated in promoting tumor metastasis.
Raf: Role in Radio- and Chemoresistance
An essential strategy for any novel targeted anticancer agent involves the abrogation of tumor cell resistance to treatment-induced growth inhibition and cell death. Such resistance has hindered the clinical effectiveness of standard radiotherapy and cytotoxic chemotherapies. However, resistance has also been observed with targeted agents like imatinib, which act by blocking a single target within the tumor (bcr-abl in chronic myelogenous leukemia, c-kit in gastrointestinal stromal tumors
Raf as a Target for Anticancer Agents
The concept of Raf-targeted disruption of cell signaling for therapeutic purposes was first advanced in 1989 with the demonstration of tumor growth inhibition in athymic mice.116 Several agents have been designed that target Raf and are in various stages of clinical development.
Targeting Melanoma With Sorafenib
The high incidence of activating B-Raf mutations in melanoma makes sorafenib an attractive agent for the treatment of this disease, especially because preclinical data suggest that B-Raf inhibition can affect melanoma growth and survival. However, in a small phase II trial of sorafenib monotherapy, in which the drug was given to patients with metastatic melanoma at a dose of 400 mg orally twice per day in 12-week cycles, there was only one PR and three cases of SD among 20 patients.130 Although
Molecular Basis of RCC: Rationale for Targeting Raf With Sorafenib
Loss of function of the VHL tumor-suppressor gene, which resides on the short arm of chromosome 3, and consequent HIF-α upregulation have been observed in most cases of clear-cell RCC.133 The normal function of the VHL gene product (pVHL) is to downregulate expression of the HIF-α transcription factors under normoxic conditions.133, 134, 135, 136, 137, 138 This downregulation is achieved by pVHL forming a multi-protein complex that ubiquitinates the α-subunit of HIF, thereby targeting it for
Summary
Isoforms of the Raf kinase function both as gatekeepers to the ubiquitous Raf/MEK/ERK signaling pathway, and as direct mediators of MEK/ERK-independent cellular proliferation and survival. Dysregulated signaling through Raf-1 (NSCLC, RCC, and HCC) or through oncogenic b-raf V600E (malignant cutaneous melanoma and PTC) has been implicated in the pathogenesis and malignant phenotype of several human solid tumors that are notoriously resistant to conventional chemotherapy and radiation. Therefore,
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