TNIK overexpression is sufficient for chemoradiation resistance in limited-stage small cell lung cancer.
Academic Article
Overview
abstract
Small cell lung cancer (SCLC) is characterized by early metastasis, intrinsic chemoradiation resistance and tumor recurrence. Besides the lack of potentially targetable oncogenic drivers, therapeutic advancements are also hindered by the scarcity of surgically resected tissue specimens ideal for profiling studies. We used patient-derived xenografts (PDXs) to model SCLC chemoradiation resistance and identified chemoradiation resistance candidate genes using RNA sequencing. Additionally, we used human SCLC cell lines to confirm our in vivo results and delineate the underlying mechanism. Transcriptome profiling showed that the Traf2- and Nck-interacting kinase (TNIK) gene was consistently upregulated in an array of SCLC PDXs exposed to chemoradiation compared to monotherapy, which is consistent with previous observation of TNIK amplification in human samples. Genetic depletion (p<0.01) or pharmacological inhibition (p<0.0001) of TNIK reduced in vitro clonogenic survival of TNIKhigh SCLC cells and promoted sensitivity to chemoradiation. In vivo, pharmacological inhibition of TNIK enhanced chemoradiation sensitivity (p<0.0001) of H446 cell line-derived xenograft (CDX) in NOD-SCID mice. Furthermore, pharmacological inhibition of TNIK in vivo demonstrated sensitivity (p<0.0001) to chemoradiotherapy in LX33 PDX. These results indicate that TNIK plays a role in conferring resistance to chemoradiation in SCLC cell lines and in vivo in SCLC CDX and PDX models. Delineating the mechanism behind radiosensitization, suggested that TNIK inhibition may impair the DNA damage response in irradiated cells. Collectively, these findings suggest that TNIK may be a promising therapeutic target in limited-stage (LS) SCLC and support further investigation of TNIK inhibition in combination with standard chemoradiotherapy.
