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

Overview

MeSH Major

  • Adenocarcinoma
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Intracellular Signaling Peptides and Proteins
  • Lung Neoplasms
  • Membrane Proteins
  • Neoplasms, Experimental
  • Proto-Oncogene Proteins p21(ras)
  • Receptor Protein-Tyrosine Kinases

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 date

  • March 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/nm.4041

PubMed ID

  • 26855149

Additional Document Info

start page

  • 270

end page

  • 7

volume

  • 22

number

  • 3