Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
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
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
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Research Article Oncology Therapeutics

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

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

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Figure 2

Increased sensitivity to cisplatin in patient-derived xenograft (PDX) lung adenocarcinoma cell lines following DDR1 knockdown.

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Increased sensitivity to cisplatin in patient-derived xenograft (PDX) lu...
(A) Western blot validation of DDR1 knockdown in 2 patient-derived xenograft (PDX) cell lines (2 and 3) treated with 2 independent shRNAs (960 and 1358) against DDR1 in parallel with a shRNA control. α-Tubulin was used as loading control. Representative Western blots of 2 independent experiments are shown. (B) Comparison of IC50 values upon 72 hours cisplatin treatment between control and DDR1-knocked down PDX cell lines maintained in 2D growth conditions. Data are shown as the mean ± SEM of 3 independent experiments. The table shows decreased IC50 values (mean ± SD, n = 3) following DDR1 knockdown. (C) Cell number quantification following treatment with the indicated concentrations of cisplatin for 72 hours in control and DDR1-knocked down PDX cell lines maintained in 2D growth conditions. Data were analyzed using 2-way ANOVA followed by Bonferroni’s multiple comparison test. **P value < 0.01, ***P value < 0.001. Data are shown as the mean ± SEM of at least 3 independent experiments. (D) Comparison of IC50 values upon 72 hours cisplatin treatment between control and DDR1-knocked down PDX cell lines maintained in 3D growth conditions. Data are shown as the mean ± SEM of 3 independent experiments. The table shows decreased IC50 values (mean ± SD, n = 3) following DDR1 knockdown. (E) Cell number quantification following treatment with the indicated concentrations of cisplatin for 72 hours in control and DDR1-knocked down PDX cell lines maintained in 3D growth conditions. All values were normalized to their respective untreated controls. Data were analyzed using 2-way ANOVA followed by Bonferroni’s multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001. Data are shown as the mean ± SEM of at least 3 independent experiments. (F) Quantification of apoptosis following treatment with the indicated concentrations of cisplatin for 72 hours in control and DDR1-knocked down PDX cell lines maintained in 2D growth conditions. Data were analyzed using 2-way ANOVA followed by Bonferroni’s multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001. Data are shown as the mean ± SEM of 3 independent experiments. P value ns, nonsignificant.