Trametinib with or without Vemurafenib in BRAF Mutated Non-Small Cell Lung Cancer

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.

Effects of PHA-665752 and vemurafenib combination treatment on in�vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations

“…However, vemurafenib plus PHA-665752 inhibit cell proliferation of both cell lines, indicating that the antitumor effect of the combined treatment may be achieved by interrupting normal cell cycling profiles. The finding is in line with previous studies on inhibition of the cell cycle in gastric cancer and non-small cell lung cancer (12,13).…”

Therapeutic approach to treating patients with BRAF-mutant lung cancer: latest evidence and clinical implications

“…The MEK TKI trametinib was also effective as a single agent in V600E BRAFmutated cells [Joshi et al 2015]. The combination of vemurafenib and trametinib caused a small but significant increase in apoptosis when compared with either single agent in this in vitro study.…”

“…Adding vemurafenib was not more effective at inhibiting cell growth, but did cause a small but significant increase in apoptosis [Joshi et al 2015]. Interestingly, treatment with single-agent trametinib caused upregulation of AKT signaling in BRAF non-V600E cells only, suggesting a potential mechanism of resistance to treatment with single-agent MEK inhibition.…”

“…In the lung, preclinical studies showed that single-agent BRAF inhibition is effective in BRAF-V600-mutated NSCLC [Joshi et al 2015;Lin et al 2014]. The MEK TKI trametinib was also effective as a single agent in V600E BRAFmutated cells [Joshi et al 2015].…”

“…Targeting non-V600E BRAF mutationpositive NSCLC Preclinical cell line studies show that single-agent BRAF TKI is effective in BRAF-V600-mutated NSCLC, but not in non-V600 BRAF mutated (lung) cancer [Joshi et al 2015;Yao et al 2015]. BRAF V600-mutated cells are activated monomers when RAS activity is low, while all other activating BRAF-mutated cells function as constitutive RAS-independent dimers.…”