title: MEK1/2 inhibition elicits regression of autochthonous lung tumors induced by KRASG12D or BRAFV600E.
abstract: Genetically engineered mouse (GEM) models of lung tumorigenesis allow careful evaluation of lung tumor initiation, progression, and response to therapy. Using GEM models of oncogene-induced lung cancer, we show the striking similarity of the earliest stages of tumorigenesis induced by KRAS(G12D) or BRAF(V600E). Cre-mediated expression of KRAS(G12D) or BRAF(V600E) in the lung epithelium of adult mice initially elicited benign lung tumors comprising cuboidal epithelial cells expressing markers of alveolar pneumocytes. Strikingly, in a head-to-head comparison, oncogenic BRAF(V600E) elicited many more such benign tumors and did so more rapidly than KRAS(G12D). However, despite differences in the efficiency of benign tumor induction, only mice with lung epithelium expression of KRAS(G12D) developed malignant non-small cell lung adenocarcinomas. Pharmacologic inhibition of mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 combined with in vivo imaging showed that initiation and maintenance of both BRAF(V600E)- or KRAS(G12D)-induced lung tumors was dependent on MEK→ERK signaling. Although the tumors dramatically regressed in response to MEK1/2 inhibition, they regrew following cessation of drug treatment. Together, our findings show that RAF→MEK→ERK signaling is both necessary and sufficient for KRAS(G12D)-induced benign lung tumorigenesis in GEM models. The data also emphasize the ability of KRAS(G12D) to promote malignant lung cancer progression compared with oncogenic BRAF(V600E).
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco 94158, USA.
authors.forename: Christy L
authors.initials: CL
authors.lastname: Trejo
authors.forename: Joseph
authors.initials: J
authors.lastname: Juan
authors.forename: Silvestre
authors.initials: S
authors.lastname: Vicent
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sweet-Cordero
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D049109:Cell Proliferation; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020545:Respiratory Mucosa / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C506614:mirdametinib; D004159:Diphenylamine; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)