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TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin
Pedro Torres-Ayuso1, Elvira An2, Katherine M Nyswaner2
1Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. john.brognard@nih.gov torresayusop2@nih.gov.
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.
Insights
Targeting the protein kinase TNIK shows promise for treating lung squamous cell carcinoma (LSCC). Inhibiting TNIK reduces LSCC growth and increases cancer cell death, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lung squamous cell carcinoma (LSCC) is a prevalent cancer lacking targeted therapies.
- Genomic alterations, particularly 3q chromosome amplification, are common in LSCC.
- Identifying actionable targets within the 3q amplicon is crucial for LSCC treatment.
Purpose of the Study:
- To identify and validate TNIK (TRAF2 and NCK interacting kinase) as a therapeutic target in LSCC.
- To investigate the role of TNIK in LSCC cell growth and survival.
- To explore the therapeutic potential of TNIK inhibition in LSCC models.
Main Methods:
- Genomic analysis to identify amplified genes in LSCC.
- Genetic depletion and pharmacologic inhibition of TNIK in LSCC cell lines and patient-derived xenografts.
- Assessment of cell viability, proliferation, and apoptosis.
- Mechanistic studies involving Merlin/NF2 and focal adhesion kinase.
Main Results:
- TNIK is amplified in approximately 50% of LSCC cases.
- TNIK inhibition (genetic or pharmacologic) significantly reduced LSCC cell growth in vitro and in vivo.
- TNIK inhibition demonstrated antitumor activity and induced apoptosis in LSCC xenografts.
- Merlin/NF2 was identified as a novel TNIK substrate, with both proteins regulating focal adhesion kinase activation.
Conclusions:
- TNIK is a druggable target essential for LSCC viability.
- Targeting TNIK represents a promising therapeutic strategy for LSCC.
- Preclinical models validate the efficacy of TNIK inhibition in LSCC.
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