TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin

Abstract

Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for the treatment of LSCC. Distal amplification of the 3q chromosome is the most frequent genomic alteration in LSCC, and there is an urgent need to identify efficacious druggable targets within this amplicon. We identify the protein kinase TNIK as a therapeutic target in LSCC. TNIK is amplified in approximately 50% of LSCC cases. TNIK genetic depletion or pharmacologic inhibition reduces the growth of LSCC cells in vitro and in vivo. In addition, TNIK inhibition showed antitumor activity and increased apoptosis in established LSCC patient-derived xenografts. Mechanistically, we identified the tumor suppressor Merlin/NF2 as a novel TNIK substrate and showed that TNIK and Merlin are required for the activation of focal adhesion kinase. In conclusion, our data identify targeting TNIK as a potential therapeutic strategy in LSCC. Significance: Targeted therapies have not yet been approved for the treatment of LSCC, due to lack of identification of actionable cancer drivers. We define TNIK catalytic activity as essential for maintaining LSCC viability and validate the antitumor efficacy of TNIK inhibition in preclinical models of LSCC. This article is highlighted in the In This Issue feature, p. 1307

Switched alternative splicing events as attractive features in lung squamous cell carcinoma

“…Lung squamous cell carcinoma (LUSC) is a common aggressive malignancy arising from lung squamous epithelium and accounts for about one-third of all lung cancer cases. Nowadays, we still have no approved targeted therapies and only depend on surgery, chemotherapy, or radiotherapy for the treatment of LUSC patients [31]. Surgical intervention for patients in the early stage and adjuvant postoperative treatment for those high-risk LUSC patients would truly improve their outcome [32].…”

Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer

“…We have recently characterized amplified TNIK as a targetable vulnerability in lung SCC and demonstrated that TNIK inhibitors efficiently reduce tumor growth. Nonetheless, we identified lung SCC cell lines sensitive to TNIK depletion mediated by shRNA but not to treatment with a small molecule inhibitor, suggesting that TNIK might contribute to tumorigenesis through an activity-independent mechanism ( Torres-Ayuso et al, 2021 ). EGFR, CDK6, and several additional kinases also display catalytic-independent functions ( Rauch et al, 2011 ).…”

Mapping lung squamous cell carcinoma pathogenesis through in vitro and in vivo models

“…A number of genes located within the 3q amplicon have been highlighted as potential LUSC drivers, including SRY-box 2 (SOX2), protein kinase C iota (PRKCI), epithelial cell transforming 2 (ECT2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) 15,16 and TRAF2 and NCK interacting kinase (TNIK) 17 . Gain-and loss-of-function studies in NSCLC cell lines have shown the transcription factor SOX2 to be a master regulator of squamous identity and a lineage-survival oncogene 18 .…”