Nexavar is the only multiple kinase inhibitor that blocks the receptor tyrosine kinases VEGFR (Vascular Endothelial Growth Factor Receptor) and PDGFR (Platelet Derived Growth Factor Receptor) and the RAF serine/threonine kinases along the RAF/MEK/ERK pathway.

Mitogen-Activated Protein Kinase  Signaling Plays a Key Role in Governing Cell Proliferation, Differentiation, and Survival

MAPK signaling is transmitted along the RAS/RAF/MEK/ERK pathway as follows:

• Activation of the small Gprotein RAS recruits of RAF1 to the inner surface of the cell membrane
• RAF1 phosphorylates MEK
• MEK phosphorylates and activates ERK downstream
• Activated ERK translocates to the cell nucleus and regulates gene expression by interacting with various transcription factors

ERK expression is associated with more aggressive HCC

ERK expression in HCC is associated with

• Increased tumor size
• Histologic progression
• Intrahepatic metastasis

Uncontrolled Activation of the RAF/MEK/ERK Pathway

The mechanisms by which uncontrolled activation or aberrant signaling along the RAF/MEK/ERK pathway may promote more aggressive HCC include

• Cell immortalization/avoidance of apoptosis — upregulation of proangiogenic factors
• Growth factor–independent proliferation and insensitivity to growth-inhibitory signals
• Invasion and metastases (through stimulation of cellular motility and extracellular matrix remodeling)
• Inactivation of tumor suppressor genes
• Treatment resistance

The Biology of Advanced RCC Provides a Strong Rationale for Targeted Therapy

• Due to the inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene, vascular endothelial growth factor and platelet-derived growth factor are overexpressed in advanced RCC
• The receptors VEGF and PDGF play important roles in tumor angiogenesis
• Serine/threonine kinases within the RAF/MEK/ERK pathway play roles in both tumor angiogenesis and tumor cell proliferation in advanced RCC

As part of a broad development program, Nexavar is also currently being evaluated in randomized trials in non-small cell lung cancer, breast cancer, melanoma and other cancers. The agent is also being studied in multiple Phase 2 trials in lung, breast and other cancers, as well as in several Phase 1b trials of the agent administered in conjunction with standard chemotherapy drugs and other anticancer agents. Nexavar was discovered and is being codeveloped by Onyx and Bayer HealthCare Pharmaceuticals.

Nexavar is a novel multiple kinase inhibitor that targets proteins involved in both tumor cell proliferation and angiogenesis (the formation of new blood vessels to support cancer cell growth). In preclinical studies, Nexavar was shown to inhibit the enzyme RAF kinase, which is a critical component of the RAS pathway - an important cascade of chemical signals that controls cell division. Abnormal activation of the RAS pathway is believed to play an integral role in the genesis of many cancers. Additionally, Nexavar inhibits VEGFR-2 and PDGFR-ß, key receptors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which play important roles in angiogenesis. Nexavar also inhibits other tyrosine kinases such as c-KIT and FLT-3.