Dabrafenib Mesylate is a salt form of Dabrafenib. Dabrafenib is an inhibitor of certain mutated forms of BRAF kinase, several of which may be associated with stimulating tumour growth (e.g. the BRAF V600E mutation), and Dabrafenib is also an inhibitor of BRAF V600-mutation positive cancer cell growth, both in vitro and in vivo. 

In vitro studies demonstrated that the concentrations required for 50 % of maximum inhibition (IC50) of BRAF V600E, BRAF V600K and BRAF V600D enzymes were, respectively, 0.65, 0.5 and 1.84 nmol/L. The IC50 values for wild-type BRAF and CRAF kinases were 3.2 and 5.0 nmol/L; the inhibition of other kinases (SIK1, NEK11
and LIMK1) by dabrafenib required still higher concentrations. Dabrafenib also appeared to have an inhibitory effect on cell lines with BRAF V600R mutations^[1].

Using a kinase panel screen for more than 270 kinases, dabrafenib proved to be selective for Raf kinase, with approximately 400-fold selectivity for BRAF over 91 % of the other kinases tested. Cellular inhibition of BRAF V600E kinase by dabrafenib resulted in decreased ERK phosphorylation and inhibition of cell proliferation, which occurred via an initial arrest at the G1 phase of the cell cycle, followed by cell death. This inhibition was selective for cancer cells that specifically encode the mutation for BRAF V600E. Orally administered dabrafenib inhibited the growth of BRAF V600E-mutant melanoma (A375P) and colon cancer (Colo205) human tumour xenografts, growing subcutaneously in immunocompromised mice [2].

Dabrafenib is associated with a decrease in phosphorylated ERK (pERK) levels. After repeat doses (days 6–13) of dabrafenib 70–200 mg twice daily, the median inhibition of pERK was 83.9 % (percentage change from baseline) in paired tumour biopsy samples taken from 8 patients with incurable solid tumours, in a phase I/II study. The one patient who received dabrafenib 150 mg twice daily experienced an 86.7 % decrease in pERK levels. Moreover, 95 % of 56 patients with incurable solid tumours receiving dabrafenib 35 mg once daily—300 mg twice daily had a decreased maximum standardised value of tumour 18F-fluorodeoxyglucose (FDG) uptake from baseline (median of 60 % decrease), according to FDG-PET scans at baseline and week 2 in the phase I/II trial [3].

Combination treatment with dabrafenib and trametinib may be effective in tumours with resistance to dabrafenib monotherapy. When dabrafenib plus trametinib was administered to patients with tumour progression on BRAF inhibitor treatment, the associated decrease in melanoma antigen expression was reversed. In vitro data show that the combination of dabrafenib and trametinib is associated with inhibition of cell growth, decreased ERK phosphorylation, decreased cyclin D1 protein, and increased p27kip1 protein levels, in cell lines with acquired resistance to dabrafenib alone [4,5].

Dabrafenib was approved by the US FDA in May 2013 as a single agent treatment for unresectable or metastatic melanoma in patients with the BRAF V600E mutation (as detected by an FDA-approved test).

References

1.Gentilcore G, Madonna G, Mozzillo N. Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations[J]. BMC Cancer. 2013, 13:17.
2.Laquerre S, Arnone M, Moss K. A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B-Raf V600E mutation. 21st AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Nov 15 2009.
3.Falchook GS, Long GV, Kurzrock R. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial[J]. Lancet. 2012, 379(9829):1893–901.
4.Frederick DT, Piris A, Cogdill AP. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma[J]. Clin Cancer Res. 2013, 19(5):1225–31.
5.Greger JG, Eastman SD, Zhang V. Combinations of BRAF, MEK, and PI3 K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations[J]. Mol Cancer Ther. 2012, 11(4):909–20.