Small Molecules in Oncology

Claus Garbe, Thomas K. Eigentler, Garbe, Claus, Eigentler, Thomas K.

The activating BRAF mutation V600E and related mutations in this codon are most important for the activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway in melanoma. BRAF V600E mutations have been detected in ~40% of melanoma patients and BRAF V600K mutations in ~5% of melanoma patients. Activation of the MAPK pathway results in continuous stimulation of cell proliferation and inhibits programmed cell death. Vemurafenib (PLX4032) was developed as a low-molecular-weight molecule for the inhibition of the mutated serine-threonine kinase BRAF, and it selectively binds to the ATP-binding site of BRAF V600E kinase and inhibits its activity. The biochemical affinity of vemurafenib for mutated BRAF translates to potent inhibition of ERK phosphorylation and of cell proliferation exclusively in BRAF-mutant cell lines. In animal model experiments, it was demonstrated that vemurafenib achieved tumour regressions in cells harbouring the BRAF V600E mutation. The clinical trials with vemurafenib in unresectable metastatic melanoma in phases I, II and III for patients harbouring BRAF V600E mutations demonstrated all unexpected high objective response rates ranging between 50 and 80%. Median progression-free survival was prolonged from 2 months with dacarbazine to 7 months with vemurafenib, and median overall survival was, respectively, prolonged from 9 to 14 months. A major problem remains in the development of resistance to vemurafenib treatment after several months in the majority of patients, and multiple resistance mechanisms have already been described. Under vemurafenib treatment, about 25% of patients developed cutaneous squamous cell carcinomas of the keratoacanthoma type with low invasive potential and without the occurrence of metastasis. The overall tolerability of the drug was quite good, and many patients remained on treatment for long times. As other solid tumours like papillary thyroid cancer, colorectal cancer, non-small-cell lung cancer and ovarian cancer likewise harbour BRAF mutation, vemurafenib is also tested in these entities. In future, combinations of vemurafenib with other kinase inhibitors and with immunotherapies will improve its therapeutic potential.