Abstract 2818: Investigating the role of TNIK in the pathogenesis of lung squamous cell carcinoma

Abstract Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer with no FDA-approved targeted therapies. Platinum-based chemotherapy and immunotherapy remain the cornerstone of current treatments for advanced LSCC, and the 5-year survival rate is less than 10%. Despite abundant knowledge of the mutational landscape of LSCC, there is a paucity of effective targeted therapies. Amplification of chromosome 3q26 is the most common genomic alteration in LSCC and this leads to the overexpression of oncogenic kinases like TNIK. TNIK amplification occurs in approximately 50% of LSCC cases and is associated with tumorigenesis and therapy resistance in other cancers. Recent studies showed that TNIK maintains the survival of LSCC cells and drives LSCC progression. Furthermore, inhibiting the kinase eradicates tumor growth in TNIK-high preclinical models. These findings highlight the potential of TNIK as a therapeutic target in a subset of LSCC patients with 3q amplification. However, one major limitation of previous studies is the lack of animal models with squamous histology and patient-relevant genotypes. Therefore, we have created a novel conditional TNIK-overexpressing genetically engineered mouse model (GEMM) to better understand the roles of TNIK in tumor progression and therapy resistance in LSCC and elucidate mechanisms underlying LSCC pathogenesis. We are also producing a novel TNIK-overexpressing LSCC GEMM based on the simultaneous activation of KrasG12D and deletion of Fbxw7 (KF model). We will present validation studies such as histological and molecular profiling of our conditional TNIK GEMM and initial data on the TNIK overexpressing LSCC transgenic mouse model (KF (LSCC control) vs KF-TNIK (LSCC-TNIK) ). Citation Format: Jin Hee Chang, Dipanwita Dutta Chowdhury, Danielle N. Council, Triet Nguyen, Shreya Jagtap, Aaron Chan, Muhammad Ajmal Khan, Nick Connis, Pedro Torres-Ayuso, John Brognard, Moahmmad Rezaee, Audrey Lafargue, Christine Hann, Phuoc T. Tran. Investigating the role of TNIK in the pathogenesis of lung squamous cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2818.