Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
Marie-Julie Nokin, … , David Santamaría, Chiara Ambrogio
Marie-Julie Nokin, … , David Santamaría, Chiara Ambrogio
Published August 6, 2020
Citation Information: JCI Insight. 2020;5(15):e137869. https://doi.org/10.1172/jci.insight.137869.
View: Text | PDF
Research Article Oncology Therapeutics

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

  • Text
  • PDF
Abstract

Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive biomarkers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DDR1 is upregulated during chemotherapy both in vitro and in vivo. Moreover, analysis of a cohort of patients with LUAD suggested that high DDR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DDR1 inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.

Authors

Marie-Julie Nokin, Elodie Darbo, Camille Travert, Benjamin Drogat, Aurélie Lacouture, Sonia San José, Nuria Cabrera, Béatrice Turcq, Valérie Prouzet-Mauleon, Mattia Falcone, Alberto Villanueva, Haiyun Wang, Michael Herfs, Miguel Mosteiro, Pasi A. Jänne, Jean-Louis Pujol, Antonio Maraver, Mariano Barbacid, Ernest Nadal, David Santamaría, Chiara Ambrogio

×

Figure 3

Lung cancer patients with high DDR1 expression display decreased response to chemotherapy and metastasis-free survival.

Options: View larger image (or click on image) Download as PowerPoint
Lung cancer patients with high DDR1 expression display decreased respons...
(A) Kaplan-Meier metastasis-free survival estimates according to DDR1 levels in lung cancer patients subjected to chemotherapy. Data were obtained from www.kmplot.com/lung (28). (B) Clinical response of patients with stage II LUAD from the TCGA database harboring non-druggable oncogenic drivers. Results are plotted based on DDR1 levels (y axis) and indicated along the x axis as patients free of recurrence (n = 44) vs. recurrence (n = 15). Wilcoxon’s test was used to analyze statistical significance. *P < 0.05. (C) Crl:NU-Foxn1nu mice implanted with KRAS-mutant PDX were treated with either vehicle or standard chemotherapy based on cisplatin (3 mg/kg) and paclitaxel (20 mg/kg) administered i.p. every 5 days for 3 weeks (n = 6). After necropsy, tumor samples were fixed and analyzed for DDR1 expression by immunostaining. Clones showing high DDR1 expression are observed in the chemotherapy-treated tumors. Scale bar: 50 μm. (D) Differential DDR1 expression in chemoresistant tumor propagating cells (TPCs) vs. the tumor bulk population (non-TPC). Gene expression data was obtained from GSE46439 (29). Wilcoxon’s test P value is indicated above the box plots. (E and F) Samples from 6 patients with LUAD with lymph node metastasis were classified, following treatment, according to the persistence (nonresponders, n = 3) or absence (responders, n = 3) of the initial lymph node metastasis. Overall DDR1 expression and the activating phosphorylation (Y-792) were evaluated in these samples by qPCR (E) or by Western blot (F). GAPDH was used as loading control. High DDR1 expression shows significant association with poor clinical response. Data were analyzed using unpaired Student’s t test. *P < 0.05. Data are shown as the mean ± SEM.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts