title: 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.
authors.affiliation: Penn State Hershey Cancer Institute, Hershey, Pennsylvania, United States of America.
authors.forename: Monika
authors.initials: M
authors.lastname: Joshi
authors.affiliation: Penn State Hershey Cancer Institute, Hershey, Pennsylvania, United States of America.
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Rice
authors.affiliation: Penn State Hershey Cancer Institute, Hershey, Pennsylvania, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Penn State Hershey Cancer Institute, Hershey, Pennsylvania, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Miller
authors.affiliation: Penn State Hershey Cancer Institute, Hershey, Pennsylvania, United States of America.
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D000069347:Erlotinib Hydrochloride; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D015854:Up-Regulation / Q000187:drug effects; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D011799:Quinazolines; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; D000069347:Erlotinib Hydrochloride; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt