1. Antitumor activity of an engineered decoy receptor targeting CLCF1–CNTFR signaling in lung adenocarcinoma
- Author
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Cesar P Marquez, Amanda Koehne, David R. Simpson, Joseph B. Shrager, Alex G. Lee, Leanne C. Sayles, Jennifer R. Cochran, Silvestre Vicent, Irene Ferrer, Luis Paz-Ares, Melanie Hayden Gephart, Kaja Kostyrko, Kim Jun Woo, Kieren D. Marini, E. Alejandro Sweet-Cordero, and Stanley G. Leung
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Adenocarcinoma of Lung ,Guanosine triphosphate ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Proto-Oncogene Proteins p21(ras) ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Neurotrophic factors ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Cell Proliferation ,Tumor microenvironment ,Interleukins ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cytokine ,Mechanism of action ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Cytokines ,Adenocarcinoma ,KRAS ,Tumor Suppressor Protein p53 ,medicine.symptom ,Ciliary Neurotrophic Factor Receptor alpha Subunit ,Protein Binding ,Signal Transduction - Abstract
Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.
- Published
- 2019