Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma.

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.

• Authors: Jun W Kim, Cesar P Marquez, Kaja Kostyrko, Amanda L Koehne, Kieren Marini, David R Simpson, Alex G Lee, Stanley G Leung, Leanne C Sayles, Joseph Shrager, Irene Ferrer, Luis Paz-Ares, Melanie Hayden Gephart, Silvestre Vicent, Jennifer R Cochran, E Alejandro Sweet-Cordero
• Journal: Nature medicine (Nat Med) Vol. 25 Issue 11 Pg. 1783-1795 (11 2019) ISSN: 1546-170X [Electronic] United States
• PMID: 31700175 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CLCF1 protein, human
• CNTFR protein, human
• Ciliary Neurotrophic Factor Receptor alpha Subunit
• Cytokines
• Interleukins
• KRAS protein, human
• Trp53 protein, mouse
• Tumor Suppressor Protein p53
• Proto-Oncogene Proteins p21(ras)

Topics

• Adenocarcinoma of Lung (drug therapy, genetics, pathology)
• Animals
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Ciliary Neurotrophic Factor Receptor alpha Subunit (chemistry, genetics)
• Cytokines (chemistry, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Interleukins (genetics)
• Mice
• Mutation (genetics)
• Protein Binding
• Proto-Oncogene Proteins p21(ras) (genetics)
• Signal Transduction (drug effects)
• Tumor Microenvironment (drug effects)
• Tumor Suppressor Protein p53 (genetics)
• Xenograft Model Antitumor Assays