How Zelboraf (Vemurafenib), a New FDA-Approved Therapy, Extends Life for Patients With Metastatic Melanoma

Paul B. Chapman, MD


The Melanoma Letter. 2011;29(2):2,3,4,6 

In This Article

The MAP Kinase Pathway

One of the primary evolutionary problems a eukaryotic cell had to overcome was how to transmit extra cellular signals from the cell surface to the nucleus. One of the primary pathways that evolved was the MAP kinase (MAPK) pathway (Figure 1a). When a ligand binds to the appropriate receptor tyrosine kinase, a conformational change is induced that leads to the phosphorylation and activation of Ras (H, N, and K). Activated Ras induces the dimerization of the Raf kinases (A, B, and C) as well as their phosphorylation. These activated dimers phosphorylate MEK, which phosphorylates ERK. Activated ERK enters the nucleus and acts as a transcription factor, turning on the transcription of several genes that lead to cellular proliferation and survival. There is also a complicated negative feedback mechanism that keeps this system under control.

Figure 1a.

The Mitogen-Activated Protein Kinase (MAPK) Pathway

When bound by their ligand, various receptor tyrosine kinases lead to ERK activation, which triggers cell proliferation and anti-apoptotic pathways. ERK also activates DUSP (dual-specificity phosphatases) and Sprouty, which negatively feed back on ERK and RAS, respectively. In melanomas with BRAFV600E mutations, the MAPK pathway is activated from the level of RAF.
Adapted from Pratilas and Solit, Clin Cancer Res 2010; 16:3329, with permission.

Approximately 50 percent of melanomas harbor an activating mutation in the BRAF gene that leads to an activating mutation of the valine at position 600, usually to glutamic acid (V600E) but sometimes to arginine or lysine. In these cells, the MAPK pathway is constitutively activated, being driven by this mutated BRAF kinase. These cells do not have activated Ras, so the Raf kinases are not dimerized. This is an important mechanism for the specificity of BRAF inhibitors.

Vemurafenib (also known as PLX4032), binds to the ATP-binding site of mutated BRAF and locks it into an active conformation, but without ATP, the mutated BRAF cannot phosphorylate downstream MEK and the MAPK pathway is turned off.

However, vemurafenib can also bind to CRAF and to a lesser degree, wild-type BRAF.[2] In the wild-type cell, the Raf kinases are dimerized, and when vemurafenib binds to wild-type CRAF or BRAF, this conformational change induces a conformational change in the other member of the dimer pair resulting in transactivation and increased MAPK pathway activity.[3] Thus, the specificity of vemurafenib comes from the fact that in cells with BRAF mutations, the cell is driven by activated BRAF, which exists primarily as monomers and is inhibited by the drug (Figure 1b). This model is supported by data from several in vitro studies.

Figure 1b.

Activity of RAF Kinase

In a quiescent, wild-type cell, RAF exists as monomers with only a limited ability to activate MEK (1). When upstream RAS is activated (typically as a result of a ligand binding to a receptor tyrosine kinase), RAF dimerizes, which results in enhanced ability to activate MEK (2). If vemurafenib is added, it binds to the ATP-binding site of one of the RAF molecules, leading to a conformational change that inactivates that molecule but further activates the associated RAF molecule (transactivation) (3). This leads to a further enhancement of MEK activation. If excess drug is added, both RAF molecules can be blocked, leading to shutdown of the pathway (4). However, it is thought that the concentration needed to achieve this is beyond the maximal tolerated dose in humans. In a cell with a BRAFV600E mutation, there is no upstream RAS activation, so the RAF molecules are not dimerized (5). The mutation is sufficient to drive the pathway. However, if vemurafenib is added, the monomers are inhibited, and since there is no dimerization, transactivation does not occur (6).
From Poulikakos and Rosen, Cancer Cell 2011; 19:11, with permission.


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