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 KrasG12V-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.
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Acknowledgements
We thank T. Hoey (OncoMed Pharmaceuticals) for providing us with demcizumab and for critical analysis of the data, as well as A. Vivancos (VHIO) for MiSeq analysis. We are thankful to S. Lee (Massachusetts General Hospital and Harvard University) for advice and reagents. We are grateful to O. Kocher, R. Pal and M. Joseph (Beth Israel Deaconess Medical Center) for help with LCM. This work was supported by grants from the European Research Council (ERC-AG/250297-RAS AEAD), the EU-Framework Programme (LSHG-CT-2007-037665/CHEMORES; HEALTH-F2-2010-259770/LUNGTARGET; and HEALTH-2010-260791/EUROCANPLATFORM), the Spanish Ministry of Economy and Competitiveness (SAF2011-30173 and SAF2014-59864-R), the Autonomous Community of Madrid (S2011/BDM-2470/ONCOCYCLE) and an Endowed Chair from the AXA Research Fund (all to M.B.), Fondo de Investigaciones Sanitarias FIS (PI13-01339 and Oncoprofile) and Fundación Mutua Madrileña AP150932014 (to A.Villanueva), a Juan Rodés fellowship from the Carlos III Health Institute (JR13/0002) and Fondo de Investigaciones Sanitarias (FIS PI14-01109) (to E.N.), the National Science Fund for Distinguished Young Scholars of China (81425021; to K.D.) and a postdoctoral fellowship from the Spanish Association Against Cancer, AECC (to C.A.). We thank R. Chiarle, T. Cash, S. Marro, M.L. De Bonis and A. Maraver for their critical reading of the manuscript and L. Paz-Ares for constructive discussion.
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C.A., D.S., A.Villanueva, M.S., M.H. and M.B. designed experiments, analyzed data and wrote the manuscript. C.A., M.F., A.Villanueva, P.J.F.-M., N.C. and R.B.B. performed experiments and analyzed the data. G.G.-L. performed all bioinformatic studies and did analysis. K.D., X.R. and Z.W. developed and provided the DDR1 inhibitor 7rh. M.S.-C. provided clinical samples and advice. A.Vidal performed human histopathological analysis. E.N. generated and evaluated clinical data.
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Significantly enriched gene pathways found in H2 versus H1 signatures. (XLSX 17 kb)
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Ambrogio, C., Gómez-López, G., Falcone, M. et al. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat Med 22, 270–277 (2016). https://doi.org/10.1038/nm.4041
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DOI: https://doi.org/10.1038/nm.4041
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