Potential role of sorafenib in the treatment of acute myeloid leukemia

Abstract

The identification of aberrant cellular pathways and dysfunctional molecules important in neoplastic transformation has begun to provide us with a number of targets for drug development. It is likely that many of these agents will be incorporated into our existing treatment strategies that include cytotoxic agents. Sorafenib, a multi-kinase inhibitor has been approved in the United States for the treatment of renal cell carcinoma as well as hepatocellular cancer. Its potential role in hematological malignancies, particularly acute myeloid leukemia (AML) is under evaluation. Here we describe the biological pathways in AML that are the potential targets of sorafenib action and discuss the early clinical data with the agent in solid tumors and AML.

Figure 1

The Ras/Raf/Mek/Erk (MAPK) pathway. Ligand-mediated activation of RTK via G-protein coupled mechanism activates RAS. Through a series of phosphorylations and dephosphorylations ultimately resulting in ERK activation, the survival signal results in differentiation and proliferation. Over activation, however, leads to oncogenesis in conjunction with G1 escape via amplification or de-regulation of nuclear transcription factor targets such as myc and AP-1.

Figure 2

Interaction of RAS/AKT proteins with apoptotic and survival signals. The pro-survival Bcl-2 proteins prevent mitochondrial mediated release of cytochrome c and thus activation of caspases whereas the pro-death proteins including Bim and Bad, Bax and Bak release apoptotic factors from the mitochondria. Bad in the non-phosphorylated state associates with Bcl-2 or Bcl-XL, promoting apoptosis. Akt and ERK phosphorylate Bad and allow its sequestration and thus inhibition of apoptosis. MCL-1 is a negative regulator of apoptosis, which acts by directly binding with BH3-only proteins such as Bim and inhibiting cytochrome c release and subsequent activation of caspases and the apoptotic cascade.

Figure 3

The structure of FLT3. FLT3 has 5 immunoglobulin-like chains that make up the extracellular ligand-binding motif, a transmembrane domain and a cytoplasmic portion composed of a kinase domain interrupted by a kinase insert. The juxtamembrane domain is where the ITDs occur.