Abstract
BackgroundCurrently, there are no available targeted therapy options for non-V600 BRAF mutated tumors. The aim of this study was to investigate the effects of RAF and MEK concurrent inhibition on tumor growth, migration, signaling and apoptosis induction in preclinical models of non-V600 BRAF mutant tumor cell lines.MethodsSix BRAF mutated human tumor cell lines CRL5885 (G466 V), WM3629 (D594G), WM3670 (G469E), MDAMB231 (G464 V), CRL5922 (L597 V) and A375 (V600E as control) were investigated. Pan-RAF inhibitor (sorafenib or AZ628) and MEK inhibitor (selumetinib) or their combination were used in in vitro viability, video microscopy, immunoblot, cell cycle and TUNEL assays. The in vivo effects of the drugs were assessed in an orthotopic NSG mouse breast cancer model.ResultsAll cell lines showed a significant growth inhibition with synergism in the sorafenib/AZ628 and selumetinib combination. Combination treatment resulted in higher Erk1/2 inhibition and in increased induction of apoptosis when compared to single agent treatments. However, single selumetinib treatment could cause adverse therapeutic effects, like increased cell migration in certain cells, selumetinib and sorafenib combination treatment lowered migratory capacity in all the cell lines. Importantly, combination resulted in significantly increased tumor growth inhibition in orthotropic xenografts of MDAMB231 cells when compared to sorafenib - but not to selumetinib – treatment.ConclusionsOur data suggests that combined blocking of RAF and MEK may achieve increased therapeutic response in non-V600 BRAF mutant tumors.
Highlights
There are no available targeted therapy options for non-V600 BRAF mutated tumors
The growth inhibitory effect of sorafenib was similar among the cell lines, except the double mutant WM3629, which was more sensitive compared to the other cells (Fig. 1b)
A375 cell line showed an elevated apoptotic effect in response to combined treatment. These results indicate that RAF and MEK1/2 vertical inhibition increases the potential to trigger apoptosis in non-V600 and V600E BRAF mutant cells
Summary
There are no available targeted therapy options for non-V600 BRAF mutated tumors. The aim of this study was to investigate the effects of RAF and MEK concurrent inhibition on tumor growth, migration, signaling and apoptosis induction in preclinical models of non-V600 BRAF mutant tumor cell lines. More than 80% of BRAF mutations are single amino acid substitutions of valin for RAS/RAF/MEK/ERK pathway vertical inhibition in treatment of V600 BRAF mutant melanoma is already approved in clinical practice. Recent studies have shown that in NRAS mutant melanoma, RAS/RAF/MEK/ERK pathway vertical inhibition leads to a synergistic inhibitory effect [9, 10]. MEK and ERK1/2 combination inhibition induced a high level of apoptosis in NRAS mutant melanoma cell lines [10]. In KRAS mutant colorectal and lung cancer cell lines RAF and MEK combination inhibition abrogates ERK1/2 signaling and triggers apoptosis [11]. Enhanced therapeutic effects of MEK inhibitor and pan-RAF inhibitor (sorafenib) combination therapies have already been described in hepatocellular, thyroid, lymphoma and renal carcinoma [12,13,14,15]
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