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

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 bioma ricers are needed for better patient stratification and fo...

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Bibliographic Details
Authors: Nokin, Marie-Julie, Darbo, Elodie, Travert, Camille, Drogat, Benjamin, Lacouture, Aurélie, San José, Sonia, Cabrera, Nuria, Turcq, Béatrice, Prouzet-Mauleon, Valérie, Falcone, Mattia, Villanueva Garatachea, Alberto, Wang, Haiyun, Herfs, Michael, Mosteiro, Miguel, Jänne, Pasi A., Pujol, Jean-Louis, Maraver, Antonio, Barbacid, Mariano, Nadal, Ernest, Santamaria, David, Ambrogio, Chiara
Format: article
Status:Published version
Publication Date:2020
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/173471
Online Access:https://hdl.handle.net/2445/173471
Access Level:Open access
Keyword:Càncer de pulmó
Quimioteràpia
Lung cancer
Chemotherapy
Description
Summary: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 bioma ricers 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 DORT is upregulated during chemotherapy both in vitro and in viva. Moreover, analysis of a cohort of patients with LUAD suggested that high DOR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DORI 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.

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