title: Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma.
abstract: Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS;TP53-mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma.
authors: Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: Chiara
authors: C
authors: Ambrogio
authors: Bioinformatics Unit, Structural Biology and Biocomputing Programme, CNIO, Madrid, Spain.
authors: Gonzalo
authors: G
authors: Gómez-López
authors: Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: Mattia
authors: M
authors: Falcone
authors: Department of Pathology, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.|Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, Barcelona, Spain.
authors: August
authors: A
authors: Vidal
authors: Thoracic Oncology Unit, Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain.
authors: Ernest
authors: E
authors: Nadal
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Nicola
authors: N
authors: Crosetto
authors: Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: Rafael B
authors: RB
authors: Blasco
authors: Tumour Suppression, Molecular Oncology Programme, CNIO, Madrid, Spain.
authors: Pablo J
authors: PJ
authors: Fernández-Marcos
authors: Cancer Epigenetics and Biology Program (PEBC), IDIBELL, Barcelona, Spain.
authors: Montserrat
authors: M
authors: Sánchez-Céspedes
authors: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Xiaomei
authors: X
authors: Ren
authors: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Zhen
authors: Z
authors: Wang
authors: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Ke
authors: K
authors: Ding
authors: Gastrointestinal Cancer Clinical Research Unit, CNIO, Madrid, Spain.
authors: Manuel
authors: M
authors: Hidalgo
authors: Tumour Suppression, Molecular Oncology Programme, CNIO, Madrid, Spain.
authors: Manuel
authors: M
authors: Serrano
authors: Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, Barcelona, Spain.|Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
authors: Alberto
authors: A
authors: Villanueva
authors: Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: David
authors: D
authors: Santamaría
authors: Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: Mariano
authors: M
authors: Barbacid
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D000069439:Dasatinib / Q000494:pharmacology; D000070819:Discoidin Domain Receptor 1; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051880:Receptors, Notch; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C064045:delta protein; C083249:Ddr1 protein, mouse; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D017239:Paclitaxel; D002945:Cisplatin; D000069439:Dasatinib; C000609115:demcizumab