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Antitumor activity of an engineered decoy receptor targeting CLCF1–CNTFR signaling in lung adenocarcinoma
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Antitumor activity of an engineered decoy receptor targeting CLCF1–CNTFR signaling in lung adenocarcinoma
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Journal Article
Antitumor activity of an engineered decoy receptor targeting CLCF1–CNTFR signaling in lung adenocarcinoma
2019
Overview
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.
A first-in-class engineered receptor decoy that neutralizes CLCF1–CNTFR signaling exhibits antitumor activity in preclinical models of lung adenocarcinoma driven by some mutant
KRAS
variants and other oncogenic genotypes.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Adenocarcinoma of Lung - drug therapy
/ Adenocarcinoma of Lung - genetics
/ Adenocarcinoma of Lung - pathology
/ Animals
/ Biomedical and Life Sciences
/ Cell Proliferation - genetics
/ Ciliary Neurotrophic Factor Receptor alpha Subunit - chemistry
/ Ciliary Neurotrophic Factor Receptor alpha Subunit - genetics
/ Gene Expression Regulation, Neoplastic - drug effects
/ Humans
/ Ligands
/ Lungs
/ Medicine
/ Mice
/ Mutation
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Signal Transduction - drug effects
/ Tumor Microenvironment - drug effects
/ Tumor Suppressor Protein p53 - genetics
/ Tumors
