Anti-tumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma

Pro-inflammatory cytokines in the tumor microenvironment (TME) can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the CLCF1-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 an autochthonous, highly aggressive genetically-engineered mouse model (GEMM) 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 effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze GTP, suggesting that the mechanism of action may be related to altered GTP 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 TME.