The Impact of Targeting TRAF2 and NCK-Interacting Protein Kinase on Antitumor Effect and Tumor Immune Environment in c-MYC-High SCLC

Authors

Azusa Tanimoto
Kavya Ramkumar
C Allison Stewart
Bingnan Zhang
Kyle Concannon
Robert J Cardnell
Li Shen
Qi Wang
Jing Wang
Carl M Gay
Lauren Averett Byers

Language

English

Publication Date

12-26-2025

Journal

Journal of Thoracic Oncology

DOI

10.1016/j.jtho.2025.12.102

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 IC50 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-MYChigh 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-MYChigh 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-MYChigh 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-MYChigh SCLC.

Keywords

CCL2, FOXK1, SCLC, TNIK, c-MYC

Published Open-Access

yes

Recommended Citation

Tanimoto, Azusa; Ramkumar, Kavya; Stewart, C Allison; et al., "The Impact of Targeting TRAF2 and NCK-Interacting Protein Kinase on Antitumor Effect and Tumor Immune Environment in c-MYC-High SCLC" (2025). Faculty, Staff and Student Publications. 5404.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5404