BRAF-tspecific inhibitors are increasingly used in advanced melanoma however; paradoxical activation of the MAPK signalling which leads to proliferation of KRAS mutant squamous cell carcinoma as a side effect has been widely reported. Newer-generation of BRAF inhibitors that does not present such potential side effect are now available.
Here we reported a proliferation of KRAS mutant colon cancer on a melanoma patient receiving a combo-treatment of BRAF inhibitor dabrafenib (GSK211436) and trametinib (GSK2118436). The solid tumor mass was succesfully resected and the cell line LM-Col-1 was consequently established. In vitro study of the older BRAF inhibitors and the newer-generation of BRAF inhibitors were conducted on a panel of cell lines with differing BRAF and RAS mutation status, including the LM-Col-1 cell line.
The in vitro study demonstrated paradoxical phosphorylation of the ERK signalling protein and enhance proliferation when treated with the older generation of BRAF inhibitors. In contratst, trametinib inhibited both phosphorylation and proliferation. Combinations of the inhibitors either induced or inhibited proliferation depending on the relative concentration of each inhibitor. The newer-generation of BRF inhibitors (non-paradoxically activating) showed no enhanced phosphorylation of the MAPK signalling pathway nor on proliferation.
In this study, we concluded that the old generation of BRAF inhibitors may paradoxically enhance MAPK signalling and proliferation in KRAS mutant adenocarcinoma however; the newer-generation of BRAF inhibitors appear to have no such paradoxicaly activation effect, which may demonstrate a potential safe ise for these inhibitors in at-risk populations.