Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
Molecular Cancer Therapeutics (Impact Factor: 5.68). 07/2010; 9(7):2090-101. DOI: 10.1158/1535-7163.MCT-10-0073
Source: PubMed


Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 micromol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.

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    • "In oncology, experimental therapies in humans and in animal experiments have shown that tumor treatment may be more effective when combining standard chemotherapy with biologicals, immunomodulating agents or cell-based immunotherapies. For example, the multiple kinase inhibitor sorafenib can improve melanoma chemotherapy in animal models [34]. Combining the contact sensitizer DNCB with dacarbazine is a strategy which improves chemotherapy in mice [35] and humans [36] by inducing a T-cell dependent immune response [37]. "
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    PLoS ONE 04/2013; 8(4):e62168. DOI:10.1371/journal.pone.0062168 · 3.23 Impact Factor
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    • "Consistent with previous studies (Augustine et al, 2010; Huber et al, 2011), however, another antiapoptotic protein, Mcl-1, was significantly downregulated by sorafenib either alone or in combination with OGX-011. Furthermore, an almost complete inactivation of Akt and p44/42 MAPK, signal transduction pathways with a potential impact on the proliferation of cancer cells, was observed in ACHN cells after combined treatment with OGX-011 and sorafenib. "
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    British Journal of Cancer 05/2012; 106(12):1945-52. DOI:10.1038/bjc.2012.209 · 4.84 Impact Factor
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    • "Various studies have shown the potential of sorafenib in inhibiting the growth of a host of malignancies including melanoma, leukemia, hepatocellular carcinoma, esophageal carcinoma in vitro and in vivo (Wilhelm et al., 2004; Sharma et al., 2005), and is successfully utilized in the treatment of renal cell carcinoma (Escudier et al., 2009). Single agent sorafenib for melanoma treatment has been largely unsuccessful, with efficacy improved when used in conjunction with chemotherapy or adjuvant immunotherapy (Eisen et al., 2006; McDermott et al., 2008; Amaravadi et al., 2009; Augustine et al., 2010; Ott et al., 2010; Egberts et al., 2011). Small molecule inhibitors with greater specificity to mutant BRAF V600E than the wild-type protein have been developed. "
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