Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma
Jun W Kim1, Cesar P Marquez2,3, Kaja Kostyrko2
1Department of Bioengineering, Stanford University, Stanford, CA, USA.
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.
Insights
Blocking cardiotrophin-like cytokine factor 1 (CLCF1) with a novel soluble receptor (eCNTFR-Fc) inhibits lung adenocarcinoma (LUAD) growth. This targeted therapy is most effective in KRAS-mutated LUAD, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Proinflammatory cytokines in the tumor microenvironment can drive tumor progression.
- The cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis plays a role in lung adenocarcinoma (LUAD).
- Targeting cytokine signaling in cancer remains an underexploited therapeutic avenue.
Purpose of the Study:
- To validate the functional role of the CLCF1-CNTFR axis in LUAD.
- To develop and test a novel therapeutic agent targeting CLCF1.
- To investigate the efficacy of CLCF1 blockade in preclinical LUAD models.
Main Methods:
- Generation of a high-affinity soluble receptor, eCNTFR-Fc, to sequester CLCF1.
- Evaluation of eCNTFR-Fc efficacy in multiple LUAD xenograft models.
- Assessment of eCNTFR-Fc in an autochthonous, genetically engineered mouse model of LUAD (Kras-driven, Trp53-null).
Main Results:
- eCNTFR-Fc effectively inhibits tumor growth in various LUAD models.
- Therapeutic efficacy is most pronounced in LUAD driven by oncogenic KRAS mutations.
- The effectiveness correlates with KRAS mutations retaining guanosine triphosphate (GTP) hydrolysis capacity, suggesting a mechanism linked to GTP loading.
Conclusions:
- Blockade of the CLCF1-CNTFR signaling pathway is a promising therapeutic strategy for LUAD.
- eCNTFR-Fc demonstrates significant preclinical anti-tumor activity, particularly in KRAS-mutated LUAD.
- Targeting CLCF1 represents a novel therapeutic opportunity for LUAD and potentially other cancers with CLCF1 presence.
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