TAZ represents a novel therapeutic target in NSCLC

Jul 16 2014

By Laura Cowen, medwireNews Reporter

Patients with non-small-cell lung cancer (NSCLC) who express high levels of transcriptional coactivator with PDZ-binding motif (TAZ) may be a clinically distinct subgroup with an unfavourable prognosis, researchers report.

TAZ, also known as WW-domain containing transcription regulator-1, plays a role in lung morphogenesis and homeostasis and has recently been suggested as an oncogene in NSCLC, explain Akira Saito (The University of Tokyo, Japan) and colleagues.

To investigate further, Saito and team initially measured TAZ expression in tumour samples from 196 patients in the well-characterised Uppsala lung cancer cohort.

They showed that increased TAZ expression correlated with squamous cell carcinoma histology and younger age. In addition, TAZ expression levels were lower in tumour samples harbouring epidermal growth factor receptor (EGFR) mutations than in mutation-negative samples.

Their current multivariate analysis, adjusted for prognostic parameters such as stage, performance status and age, showed that high TAZ expression was associated with decreased survival (hazard ratio for death=1.24). And this finding was confirmed in a meta-analysis of nine independent lung cancer sets (n=1382 patients) where higher TAZ mRNA levels were associated with shorter survival, at a hazard ratio of 1.21.

Immunohistochemistry studies of protein expression, performed by the researchers on tissue samples from 345 patients with NSCLC and 18 cancer-free controls, corresponded with these findings.

Interestingly, alveolar and bronchial epithelial cells from the nonmalignant lung tissue samples all showed positive nuclear staining for TAZ protein, whereas the lung cancer tissues revealed variable staining patterns, ranging from strongly positive to completely negative.

“These results indicated differential expression of TAZ in NSCLC and suggested that high TAZ expression at the genomic, mRNA, and protein levels might define a clinical subset of NSCLC patients”, write Saito and co-authors in Clinical Cancer Research.

Further in vitro analyses showed that transduction of TAZ enhanced cell proliferation and tumourigenesis in bronchial epithelial cells, while TAZ silencing suppressed cell proliferation and induced cell cycle arrest in NSCLC cells.

Microarray-based expression profiling analysis, carried out in A549 lung cancer cells after TAZ knockdown, revealed that the downstream targets of TAZ include the cell cycle regulators cyclin D1 and D3, as well as the EGFR ligands amphiregulin, epiregulin and neuregulin 1. This suggests that “TAZ activates the EGFR signaling pathway through the induction of EGFR ligands”, the researchers remark.

They conclude that their results “not only confirm the clinical relevance of TAZ in NSCLC patients but also offer a conceptual basis for novel therapeutic strategies in subgroups of NSCLC patients.”

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