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Characterization of the protein kinase TNIK as a new therapeutic target for lung squamous cell carcinoma

Wednesday, September 12, 2018 — Poster Session II

3:30 p.m. – 5:00 p.m.
FAES Terrace
NCI
CANCER-34

Authors

  • P Torres-Ayuso
  • E An
  • R Liang
  • K Nyswaner
  • J Brognard

Abstract

Lung squamous cell carcinoma (LSCC) is the second most common form of lung cancer. Although significant advances have been made to understand the genetic landscape and biology of this tumor type, there are still no targeted therapies approved for LSCC due to lack of identification of bona fide druggable genetic drivers or actionable gain-of-function mutations. Protein kinases are amenable targets for therapeutic intervention, an important subset of FDA-approved cancer treatments are kinase inhibitors. We have pinpointed the serine/threonine protein kinase TNIK (Traf2- and Nck-interacting kinase) as a potential driver gene of LSCC. The TNIK gene is frequently amplified and/or overexpressed in LSCC patients. We hypothesized that increased TNIK expression, and activity, will be required to maintain LSCC progression and cell survival. Using functional assays, and a combination of shRNA-mediated knockdown and small molecule inhibitors, we have determined that TNIK downregulation abrogates the growth of LSCC cells with high TNIK expression. To investigate the mechanisms that TNIK regulates to promote LSCC viability, we have used a combination of reverse phase protein arrays and mass spectrometry. This has revealed that TNIK modulates the tumor suppressor Merlin. Currently, we are generating novel patient-derived preclinical models, including organoids and patient-derived xenografts, to validate TNIK inhibitors as a therapeutic strategy for LSCC treatment in vivo. In conclusion, we have characterized increased TNIK expression as a druggable dependency in LSCC. In the future, we will assess whether increased TNIK levels could serve as a biomarker to select patients that would benefit from treatment with TNIK inhibitors.

Category: Cancer Biology