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(50) 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(high) 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(high) 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(high) 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(high) SCLC.