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Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma

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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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Figure 1: Gene expression profiling of KrasG12V-driven hyperplasias.
Figure 2: KrasG12V-driven lung tumorigenesis is delayed in the absence of Ddr1.
Figure 3: Pharmacological inhibition of DDR1 induces tumor regression in DDR1+ lung adenocarcinomas.
Figure 4: Co-inhibition of DDR1 and Notch signaling induces tumor apoptosis.
Figure 5: Co-inhibition of DDR1 and Notch compared to chemotherapy.
Figure 6: Co-inhibition of DDR1 and Notch as a therapy in KRAS-driven human 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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Author notes

  1. Mattia Falcone & Rafael B Blasco

    Present address: Present addresses: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany (M.F.), and Department of Pathology, Boston Children's Hospital–Harvard Medical School, Boston, Massachusetts, USA (R.B.B.).,

Authors and Affiliations

  1. Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    Chiara Ambrogio, Mattia Falcone, Rafael B Blasco, David Santamaría & Mariano Barbacid

  2. Bioinformatics Unit, Structural Biology and Biocomputing Programme, CNIO, Madrid, Spain.,

    Gonzalo Gómez-López

  3. Department of Pathology, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain

    August Vidal

  4. Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, Barcelona, Spain

    August Vidal & Alberto Villanueva

  5. Department of Medical Oncology, Thoracic Oncology Unit, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain

    Ernest Nadal

  6. Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden

    Nicola Crosetto

  7. Tumour Suppression, Molecular Oncology Programme, CNIO, Madrid, Spain

    Pablo J Fernández-Marcos & Manuel Serrano

  8. Cancer Epigenetics and Biology Program (PEBC), IDIBELL, Barcelona, Spain

    Montserrat Sánchez-Céspedes

  9. State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Xiaomei Ren, Zhen Wang & Ke Ding

  10. Gastrointestinal Cancer Clinical Research Unit, CNIO, Madrid, Spain

    Manuel Hidalgo

  11. Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain

    Alberto Villanueva

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  1. Chiara Ambrogio
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  2. Gonzalo Gómez-López
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Contributions

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.

Corresponding authors

Correspondence to Chiara Ambrogio, David Santamaría or Mariano Barbacid.

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The authors declare no competing financial interests.

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Supplementary Figures 1–15 and Supplementary Tables 1 and 3 (PDF 20203 kb)

Supplementary Table 2

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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