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Ref Type Journal Article
PMID (25706985)
Authors Joshi M, Rice SJ, Liu X, Miller B, Belani CP
Title Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer.
Journal PloS one
Vol 10
Issue 2
Date 2015
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
BRAF G469R MEK1 Inhibitor
BRAF D594N MEK1 Inhibitor
BRAF G464E MEK1 Inhibitor
BRAF F247L MEK2 Inhibitor
BRAF G466R MEK1 Inhibitor
BRAF L597S MEK2 Inhibitor
BRAF G469A MEK1 Inhibitor
BRAF V600delinsYM MEK1 Inhibitor
BRAF V487_P492delinsA MEK1 Inhibitor
BRAF F468C MEK2 Inhibitor
BRAF T599R MEK2 Inhibitor
BRAF D594A MEK2 Inhibitor
BRAF K601T MEK1 Inhibitor
BRAF G596C MEK2 Inhibitor
BRAF F595L MEK1 Inhibitor
BRAF T599_V600insTT MEK2 Inhibitor
BRAF T599I MEK2 Inhibitor
BRAF K601N MEK2 Inhibitor
BRAF N486_P490del MEK1 Inhibitor
BRAF G466V MEK2 Inhibitor
BRAF G469del MEK2 Inhibitor
BRAF L485_P490delinsF MEK2 Inhibitor
BRAF G464E MEK2 Inhibitor
BRAF P490_Q494del MEK1 Inhibitor
BRAF L597S MEK1 Inhibitor
BRAF K601N MEK1 Inhibitor
BRAF K601I MEK2 Inhibitor
BRAF V487_P492delinsA MEK2 Inhibitor
BRAF E586K MEK2 Inhibitor
BRAF G464R MEK1 Inhibitor
BRAF L505H MEK2 Inhibitor
BRAF A598_T599insARC MEK2 Inhibitor
BRAF D287H MEK1 Inhibitor
BRAF A728V MEK1 Inhibitor
BRAF T488_Q493delinsK MEK1 Inhibitor
BRAF G466R MEK2 Inhibitor
BRAF T599R MEK1 Inhibitor
BRAF L597P MEK2 Inhibitor
BRAF G469S MEK2 Inhibitor
BRAF V600dup MEK1 Inhibitor
BRAF L485_P490del MEK2 Inhibitor
BRAF L597Q MEK1 Inhibitor
BRAF K601Q MEK1 Inhibitor
BRAF D594Y MEK1 Inhibitor
BRAF G469A MEK2 Inhibitor
BRAF G596R MEK2 Inhibitor
BRAF A598V MEK2 Inhibitor
BRAF T599_V600insETT MEK1 Inhibitor
BRAF L485_P490del MEK1 Inhibitor
BRAF A598_T599insV MEK2 Inhibitor
BRAF D594E MEK1 Inhibitor
BRAF L485_P490delinsY MEK2 Inhibitor
BRAF N486_P490del MEK2 Inhibitor
BRAF L505H MEK1 Inhibitor
BRAF G469V MEK1 Inhibitor
BRAF T599dup MEK1 Inhibitor
BRAF D594_T599dup MEK2 Inhibitor
BRAF G464R MEK2 Inhibitor
BRAF L485F MEK1 Inhibitor
BRAF E586K MEK1 Inhibitor
BRAF S467A MEK1 Inhibitor
BRAF T599dup MEK2 Inhibitor
BRAF A728V MEK2 Inhibitor
BRAF T599_V600insTT MEK1 Inhibitor
BRAF G469S MEK1 Inhibitor
BRAF L485_P490delinsF MEK1 Inhibitor
BRAF G464V MEK2 Inhibitor
BRAF Q257R MEK2 Inhibitor
BRAF T488_Q493delinsK MEK2 Inhibitor
BRAF V600_K601delinsE MEK1 Inhibitor
BRAF F468C MEK1 Inhibitor
BRAF D594_T599dup MEK1 Inhibitor
BRAF K601T MEK2 Inhibitor
BRAF L597V MEK1 Inhibitor
BRAF G469del MEK1 Inhibitor
BRAF N486_T491delinsK MEK2 Inhibitor
BRAF V600_K601delinsE MEK2 Inhibitor
BRAF act mut MEK1 Inhibitor
BRAF G596C MEK1 Inhibitor
BRAF K601I MEK1 Inhibitor
BRAF G469R MEK2 Inhibitor
BRAF G464V MEK1 Inhibitor
BRAF Q257R MEK1 Inhibitor
BRAF L597V MEK2 Inhibitor
BRAF G469L MEK2 Inhibitor
BRAF V471F MEK1 Inhibitor
BRAF K499E MEK1 Inhibitor
BRAF T599_V600insEAT MEK2 Inhibitor
BRAF T599_V600insETT MEK2 Inhibitor
BRAF G469V MEK2 Inhibitor
BRAF T488_P492del MEK2 Inhibitor
BRAF D594E MEK2 Inhibitor
BRAF V600delinsYM MEK2 Inhibitor
BRAF T488_P492del MEK1 Inhibitor
BRAF G596V MEK2 Inhibitor
BRAF S467A MEK2 Inhibitor
BRAF G469L MEK1 Inhibitor
BRAF K601E MEK1 Inhibitor
BRAF L485_Q494del MEK2 Inhibitor
BRAF R347* MEK2 Inhibitor
BRAF F595L MEK2 Inhibitor
BRAF I463S MEK1 Inhibitor
BRAF A598V MEK1 Inhibitor
BRAF V504_R506dup MEK2 Inhibitor
BRAF K601E MEK2 Inhibitor
BRAF G596R MEK1 Inhibitor
BRAF A598_T599insARC MEK1 Inhibitor
BRAF T599I MEK1 Inhibitor
BRAF F247L MEK1 Inhibitor
BRAF L485_P490delinsY MEK1 Inhibitor
BRAF D594Y MEK2 Inhibitor
BRAF D594H MEK1 Inhibitor
BRAF G596D MEK2 Inhibitor
BRAF D287H MEK2 Inhibitor
BRAF V504_R506dup MEK1 Inhibitor
BRAF A598_T599insV MEK1 Inhibitor
BRAF V600dup MEK2 Inhibitor
BRAF G596D MEK1 Inhibitor
BRAF K601Q MEK2 Inhibitor
BRAF L597P MEK1 Inhibitor
BRAF L597Q MEK2 Inhibitor
BRAF L597R MEK2 Inhibitor
BRAF I463S MEK2 Inhibitor
BRAF L485F MEK2 Inhibitor
BRAF act mut MEK2 Inhibitor
BRAF D594H MEK2 Inhibitor
BRAF N486_T491delinsK MEK1 Inhibitor
BRAF G466V MEK1 Inhibitor
BRAF G596V MEK1 Inhibitor
BRAF L485_Q494del MEK1 Inhibitor
BRAF V471F MEK2 Inhibitor
BRAF D594N MEK2 Inhibitor
BRAF D594A MEK1 Inhibitor
BRAF K499E MEK2 Inhibitor
BRAF P490_Q494del MEK2 Inhibitor
BRAF L597R MEK1 Inhibitor
BRAF T599_V600insEAT MEK1 Inhibitor
BRAF R347* MEK1 Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF G469A lung non-small cell carcinoma conflicting Trametinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the combination of Mekinist (trametinib) and Zelboraf (vemurafenib) inhibited growth of a non-small cell lung cancer cell line harboring BRAF G469A in culture, and prevented Mekinist (trametinib)-related activation of AKT and resulted in increased induction of apoptosis compared to either agent alone (PMID: 25706985). 25706985
BRAF G469A lung non-small cell carcinoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring BRAF G469A demonstrated resistance to induction of apoptosis by Zelboraf (vemurafenib,) and treatment with Zelboraf (vemurafenib) was not effective in inhibiting growth in culture (PMID: 25706985). 25706985
BRAF G469A lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) induced apoptosis and inhibited growth of a non-small cell lung cancer cell line harboring BRAF G469A in culture (PMID: 25706985). 25706985