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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics*
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Adenocarcinoma of Lung
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Aged
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Animals
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects*
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cisplatin / pharmacology
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Dasatinib / pharmacology
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Discoidin Domain Receptor 1
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Lung Neoplasms / genetics*
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Male
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Membrane Proteins / antagonists & inhibitors*
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Mice
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Middle Aged
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Mutation
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Neoplasm Transplantation
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Neoplasms, Experimental / genetics*
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Paclitaxel / pharmacology
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Proto-Oncogene Proteins p21(ras) / genetics*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptors, Notch
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptors, Notch
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delta protein
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Ddr1 protein, mouse
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Discoidin Domain Receptor 1
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Receptor Protein-Tyrosine Kinases
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Proto-Oncogene Proteins p21(ras)
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Paclitaxel
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Cisplatin
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Dasatinib
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demcizumab