Statement of the problem: Lung cancer is the second most commonly diagnosed cancer in both men and women, behind prostate and breast cancer, respectively. However, it is the leading cause of cancer death globally. Histologically, 85% of lung cancers are classified as non-small cell lung cancer (NSCLC) and the remaining 15% as small cell lung cancer (SCLC). While significant advancements have been made in developing targeted therapies for NSCLC, no targeted treatment options exist for SCLC. Concurrent chemoradiation remains the backbone of the standard of care (SOC) for limited-stage SCLC (LS-SCLC) patients. 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 paucity of surgically resected tissue specimens ideal for profiling studies. Summary of methods: 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 mechanisms. Results: 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 SCLC samples in Rudin and George genomic datasets. 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. Finally, TNIK inhibition impaired the DNA damage response in TNIKhigh SCLC cell lines post-radiation, by disrupting the ATM-CHK2 signaling pathway. Conclusions: 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 LS-SCLC and support further investigation of TNIK inhibition in combination with standard chemoradiotherapy.