title: NSCLC Driven by DDR2 Mutation Is Sensitive to Dasatinib and JQ1 Combination Therapy.
abstract: Genetically engineered mouse models of lung cancer have demonstrated an important role in understanding the function of novel lung cancer oncogenes and tumor-suppressor genes identified in genomic studies of human lung cancer. Furthermore, these models are important platforms for preclinical therapeutic studies. Here, we generated a mouse model of lung adenocarcinoma driven by mutation of the discoidin domain receptor 2 (DDR2) gene combined with loss of TP53. DDR2(L63V);TP53(L/L) mice developed poorly differentiated lung adenocarcinomas in all transgenic animals analyzed with a latency of 40 to 50 weeks and a median survival of 67.5 weeks. Mice expressing wild-type DDR2 with combined TP53 loss did not form lung cancers. DDR2(L63V);TP53(L/L) tumors displayed robust expression of DDR2 and immunohistochemical markers of lung adenocarcinoma comparable with previously generated models, though also displayed concomitant expression of the squamous cell markers p63 and SOX2. Tumor-derived cell lines were not solely DDR2 dependent and displayed upregulation of and partial dependence on MYCN. Combined treatment with the multitargeted DDR2 inhibitor dasatinib and BET inhibitor JQ1 inhibited tumor growth in vitro and in vivo. Together, these results suggest that DDR2 mutation can drive lung cancer initiation in vivo and provide a novel mouse model for lung cancer therapeutics studies.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Belfer Institute for Applied Cancer Sciences, Boston, MA, USA.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Buczkowski
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Belfer Institute for Applied Cancer Sciences, Boston, MA, USA.
authors.forename: Yanxi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Belfer Institute for Applied Cancer Sciences, Boston, MA, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Asahina
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Beauchamp
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Terai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Belfer Institute for Applied Cancer Sciences, Boston, MA, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001381:Azepines / Q000008:administration & dosage; D063646:Carcinogenesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000008:administration & dosage; D000070818:Discoidin Domain Receptors; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D020125:Mutation, Missense; D000071447:N-Myc Proto-Oncogene Protein; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011975:Receptors, Mitogen / Q000235:genetics*; D014230:Triazoles / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D011518:Proto-Oncogene Proteins; D011975:Receptors, Mitogen; D014230:Triazoles; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D000069439:Dasatinib