Abstract
V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutated lung cancer is relatively aggressive and is resistant to currently available therapies. In a recent phase II study for patients with BRAF-V600E non-small cell lung cancer (NSCLC), BRAF V600E inhibitor demonstrated evidence of activity, but 30% of this selected group progressed while on treatment, suggesting a need for developing alternative strategies. We tested two different options to enhance the efficacy of vemurafenib (BRAF V600E inhibitor) in BRAF mutated NSCLC. The first option was the addition of erlotinib to vemurafenib to see whether the combination provided synergy. The second was to induce MEK inhibition (downstream of RAF) with trametinib (MEK inhibitor). We found that the combination of vemurafenib and erlotinib was not synergistic to the inhibition of p-ERK signaling in BRAF-V600E cells. Vemurafenib caused significant apoptosis, G1 arrest and upregulation of BIM in BRAF-V600 cells. Trametinib was effective as a single agent in BRAF mutated cells, either V600E or non-V600E. Finally, the combination of vemurafenib and trametinib caused a small but significant increase in apoptosis as well as a significant upregulation of BIM when compared to either single agent. Thus, hinting at the possibility of utilizing a combinational approach for the management of this group of patients. Importantly, trametinib alone caused upregulation of p-AKT in BRAF non-V600 mutated cells, while this effect was nullified with the combination. This finding suggests that, the combination of a MEK inhibitor with a BRAF inhibitor will be more efficacious in the clinical setting for patients with BRAF mutated NSCLC.
Highlights
A majority of patients with non-small cell lung cancer (NSCLC) are diagnosed at a later stage and currently available treatments including chemotherapy and radiotherapy seem to be insufficient in beating this deadly disease
BRAF pathway plays an important role in tumorigenesis in NSCLC,BRAF inhibitors, vemurafenib and dabrafenib have shown only modest efficacy in BRAF-V600E mutant cancers [11,13]
Despite targeting this specific mutation, the use of dabrafenib, in NSCLC with BRAFV600E mutation has resulted in only a 40% response rate along with a disappointing 30% disease progression [11]. These results reflect that BRAF inhibition alone is not an ideal treatment option and newer strategies for optimized and effective treatment of this select group of patients are warranted. This hypothesis is supported by a clinical study in melanoma showing a significant advantage in progression free survival with combination of dabrafenib plus trametinib vs. dabrafenib alone [12]
Summary
A majority of patients with non-small cell lung cancer (NSCLC) are diagnosed at a later stage and currently available treatments including chemotherapy and radiotherapy seem to be insufficient in beating this deadly disease. The presence of an activating mutation in the epidermal growth factor receptor (EGFR) is associated with high response rates and improved progression free survival (PFS) with the use of EGFR tyrosine kinase inhibitors (TKIs) [1,2,3]. Erlotinib and gefitinib are first generation TKIs that cause reversible inhibition of the tyrosine kinase domain of EGFR. Erlotinib was initially approved for clinical use in advanced NSCLC in the second line setting on the basis of positive results of the phase 3 BR. trial [4].
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