The Impact of Targeting TRAF2 and NCK-Interacting Protein Kinase on Antitumor Effect and Tumor Immune Environment in c-MYC-High SCLC.
1/5 보강
[INTRODUCTION] Wnt/β-catenin signaling pathway activation contributes to tumorigenesis and chemo-resistance in SCLC, yet clinical attempts to target this pathway have been unsuccessful.
APA
Tanimoto A, Ramkumar K, et al. (2025). The Impact of Targeting TRAF2 and NCK-Interacting Protein Kinase on Antitumor Effect and Tumor Immune Environment in c-MYC-High SCLC.. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. https://doi.org/10.1016/j.jtho.2025.12.102
MLA
Tanimoto A, et al.. "The Impact of Targeting TRAF2 and NCK-Interacting Protein Kinase on Antitumor Effect and Tumor Immune Environment in c-MYC-High SCLC.." Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2025.
PMID
41456708
Abstract
[INTRODUCTION] Wnt/β-catenin signaling pathway activation contributes to tumorigenesis and chemo-resistance in SCLC, yet clinical attempts to target this pathway have been unsuccessful. TRAF2 and NCK-interacting protein kinase (TNIK), an essential nuclear activator of Wnt/β-catenin target genes, has not yet been validated as a viable therapeutic target in SCLC. Here, we validated that TNIK inhibition is a promising approach for personalized anticancer therapy in SCLC.
[METHODS] We correlated the IC values of a TNIK inhibitor, NCB-0846, with proteomic profiling (reverse phase protein array) data across 28 SCLC cell lines. Cytokine array analysis was performed to quantify changes in 105 cytokines after TNIK inhibitor treatment.
[RESULTS] We identified c-MYC expression as a top candidate marker of TNIK inhibition response. In xenograft models of c-MYC SCLC, TNIK inhibition led to suppression of tumor growth and a decrease in c-MYC expression. In the clinically aggressive POU2F3 expressing subtype of SCLC, the TNIK inhibitor demonstrated antitumor effect by decreasing SOX9 in addition to c-MYC. Furthermore, TNIK inhibition suppressed the production of the immunosuppressive chemokine CCL2 by attenuating its transcription factor FOXK1 in c-MYC SCLC cells. Combination of TNIK inhibition and an anti-PD-L1 antibody resulted in greater efficacy and reduced infiltration of immunosuppressive cells compared with each monotherapy in immunocompetent SCLC in vivo models.
[CONCLUSIONS] TNIK inhibition is more effective in c-MYC SCLC, acting through down-regulation of c-MYC levels. It also decreases the production of CCL2, supporting the rationale for combination therapy with immune checkpoint inhibitors in c-MYC SCLC.
[METHODS] We correlated the IC values of a TNIK inhibitor, NCB-0846, with proteomic profiling (reverse phase protein array) data across 28 SCLC cell lines. Cytokine array analysis was performed to quantify changes in 105 cytokines after TNIK inhibitor treatment.
[RESULTS] We identified c-MYC expression as a top candidate marker of TNIK inhibition response. In xenograft models of c-MYC SCLC, TNIK inhibition led to suppression of tumor growth and a decrease in c-MYC expression. In the clinically aggressive POU2F3 expressing subtype of SCLC, the TNIK inhibitor demonstrated antitumor effect by decreasing SOX9 in addition to c-MYC. Furthermore, TNIK inhibition suppressed the production of the immunosuppressive chemokine CCL2 by attenuating its transcription factor FOXK1 in c-MYC SCLC cells. Combination of TNIK inhibition and an anti-PD-L1 antibody resulted in greater efficacy and reduced infiltration of immunosuppressive cells compared with each monotherapy in immunocompetent SCLC in vivo models.
[CONCLUSIONS] TNIK inhibition is more effective in c-MYC SCLC, acting through down-regulation of c-MYC levels. It also decreases the production of CCL2, supporting the rationale for combination therapy with immune checkpoint inhibitors in c-MYC SCLC.