Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer.
We investigated the clinical implications of lung developmental transcription factors (TTF-1, NKX2-8, and PAX9) that we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the 3 genes were determined and used to risk stratify a non-small-cell lung cancer (NSCLC) clinical data set consisting of 91 early stage tumors. Coactivation of the TTF-1 and NKX2-8 pathways identified a cluster of patients with poor survival, representing approximately 20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with coactivation of TTF-1 and NKX2-8 was validated in 2 other independent clinical data sets. Furthermore, lung cancer cell lines showing coactivation of the TTF-1 and NKX2-8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. This suggests that the cohort of patients with coactivation of TTF-1 and NKX2-8 pathways appears to be resistant to standard cisplatin therapy, suggesting the need for alternative therapies in this cohort of high-risk patients.
Hsu
David S
DS
Institute for Genome Sciences and Policy, Department of Medicine, and Institute for Statistics and Decision Sciences, Duke University, Durham, NC 27710, USA.
Acharya
Chaitanya R
CR
Balakumaran
Bala S
BS
Riedel
Richard F
RF
Kim
Mickey K
MK
Stevenson
Marvaretta
M
Tuchman
Sascha
S
Mukherjee
Sayan
S
Barry
William
W
Dressman
Holly K
HK
Nevins
Joseph R
JR
Powers
Scott
S
Mu
David
D
Potti
Anil
A
D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D002883:Chromosomes, Human, Pair 14; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005784:Gene Amplification; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms; D009857:Oncogenes; D051764:PAX9 Transcription Factor / Q000378:metabolism*; D011379:Prognosis; D018570:Risk Assessment; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C108070:NKX2-8 protein, human; D051764:PAX9 Transcription Factor; C504003:TTF1 protein, human; D014157:Transcription Factors