PharmGKB summary: sorafenib pathways

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Excerpt

Sorafenib (Nexavar, BAY43-9006) is an oral anticancer drug approved by the US Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma (RCC), unresectable or metastatic hepatocellular carcinoma (HCC), and locally recurrent or metastatic, progressive, and differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment 1. It is also being evaluated in acute myeloid leukemia and other solid tumors in adults and children. Sorafenib inhibits tumor cell proliferation and angiogenesis by targeting numerous serine/threonine and tyrosine kinases [RAF1, BRAF, vascular endothelial growth factor receptor (VEGFR) 1, 2, 3, platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), FMS-related tyrosine kinase 3 receptor (FLT3), fibroblast growth factor receptor 1 (FGFR1), and RET proto-oncogene (RET)] in multiple oncogenic signaling pathways 2–5. The most common adverse effects associated with sorafenib include hand–foot skin reaction (HFSR), diarrhea, hypertension, rash, fatigue, abdominal pain, and nausea 6–9. Severe adverse effects (e.g. liver failure, myocardial infarction) are rare, but may arise in some cases. Adverse events may lead to compromised efficacy because of dose reduction or treatment interruptions. There is high interpatient variability in cumulative drug exposure and responses following sorafenib treatment 2,3,10,11. In this review, we discuss the clinical pharmacology of sorafenib and highlight genetic variations that may contribute toward the diverse pharmacological responses to sorafenib. Better understanding of the factors contributing toward the high variability of response to sorafenib should improve the efficacy and safety of the drug and help select patients who will benefit most from sorafenib therapy.
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