2015 Lung Cancer Research Foundation Annual Grant Program
John Brognard, PhD
University of Manchester
Research Project:
Identification and validation of a new target for lung squamous cell carcinoma treatment
Summary:
A major challenge for the research community is to translate cancer genomic sequencing data into better therapies for cancer patients. Specifically, in cancers where we lack an understanding of the genetic drivers, such as lung squamous cell carcinoma (LSCC) where we have not identified genetic drivers for over 60% of all cases, identification of these drivers and translating the information into novel therapies is an essential unmet need. Utilizing bioinformatics and high throughput screening approaches, Dr. Brognard and his team have identified a novel enzyme (TNIK) as a potential essential driver in approximately 40% of all LSCC patients. The goal of Dr. Brognard’s research is to validate these initial findings and assess if the enzyme and inhibitors targeting the enzyme could yield potential therapies for LSCC patients.
Update: January 2021
The paper outlined below was accepted in Cancer Discovery.
TNIK (TRAF2 and NCK-Interacting protein kinase) is a therapeutic target in LSCC, the second most prevalent type of lung cancer, and regulates FAK activation through Merlin. Despite extensive genomic characterization, no targeted therapies are approved for treating 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. Our lab identified the protein kinase TNIK as a therapeutic target – TNIK is amplified in approximately 50% of LSCC cases. TNIK genetic depletion or pharmacological 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, the study 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, the data supports targeting TNIK as a potential therapeutic strategy in LSCC.