Braf inhibitors

RAF is an acronym for "Rapidly growing fibrosarcoma". The BRAF gene codes for the so-called Raf proteins (kinases). Raf kinases are found in all tissues of mammals and belong to the serine/threonine protein kinases. Braf (B-raf) has been identified as a potent oncogene.

About half of all malignant melanomas and a larger number of thyroid carcinomas (as well as a number of other tumors) express a mutation in the BRAF gene. The replacement of a single amino acid (valine by glutamic acid at position 600) is associated with increased cell proliferation. This gene plays a role in melanoma formation. Remarkably, "excessive intermittent sunbathing" can lead to this "tumor-inducing" mutation.

In about 2/3 of all malignant melanomas this mutation is found. The mutation leads to permanent activation of the BRAF gene, constitutively increased kinase activity, and activated ERK. Remarkably, these BRAF mutations are found in melanomas induced by intermittent sun exposure, but not in malignant melanomas with chronic sun exposure (Landi MT et al. 2006).

However, BRAF mutations are not specific to malignant melanoma. In one study, somatic mutations of the B-RAF gene (especially the V600E mutation) were detected in 77% of the melanocytic nevi examined. The V600E BRAF mutation initially leads to an acceleration of cell senescence. This makes the cell more vulnerable to further mutations (second hit), which can then lead to malignant degeneration.

Furthermore, BRAF mutations are detectable in 50% of Langerhans cells of pulmonary Langerhans cell histiocytoses.

The BRAF gene encodes a kinase that can be inhibited by BRAf inhibitors (see below Vemurafenib, Dabrafenib,Sorafenib).

BRAF inhibition may result in paradoxical activation of the MAPK pathway due to increased stimulation of other RAF kinases. This leads to increased keratinocyte stimulation. The consequence is the unexpected appearance of non-melanotic skin tumors in almost 80% of patients: seborrheic keratoses, palmo-plantar and follicular hyperkeratoses. Rapidly growing keratoacanthomas or squamous cell carcinomas occur in 20-30% of patients.

Less common is the occurrence of eruptive melanocytic nevi, photosensitivity, or follicular maculo-papular exanthema.

Other side effects include fatigue, arthralgias, and radiation recall dermatitis.

The following BRAF inhibitors are available:

• Vemurafenib
• Dabrafenib
• Sorafenib
• Encorafenib

The BRAF inhibitor PLX 4032 (now Hoffmann La Roche), developed by the company Plexxikon in Berkeley/California, is one of the most promising candidates for the effective treatment of malignant melanoma. PLX 4032 has now been approved (see vemurafenib below). The patients treated with this drug (BRIMP study) survived an average of at least 6 months without progression of the melanoma disease (progression-free survival time). Furthermore, regressions in patients with liver, lung and bone metastases could be detected. The response rate of the tumors is thus over 80 percent. Dabrafenib is another BRAF inhibitor already approved.

1. Bloethner S et al(2007) Differential gene expression in melanocytic nevi with the V600E BRAF mutation. Genes Chromosomes Cancer 46:1019-10227
2. Landi MT (2006) MC1R germline variants confer risk for BRAF mutant melanoma. Science 313:521-522.