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| Status |
Public on Apr 01, 2009 |
| Title |
Overexpression of lung developmental transcription factors TTF-1, NKX2-8 and PAX9 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
We investigated the clinical implications of lung developmental transcription factors (TTF-1, NKX2-8, and PAX9) which 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 three genes were determined and used to risk stratify a non-small cell lung cancer (NSCLC) clinical dataset consisting of ninety-one early stage tumors. Co-activation 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 co-activation of TTF-1 and NKX2-8 was validated in two other independent clinical datasets. Further, lung cancer cell lines showing co-activation of the TTF-1 and NKX2-8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. Since TTF-1 and NKX2-8 lack specific inhibitors at the current time, we explored an alternative therapeutic strategy. Using signatures of signaling pathway activation, we identified deregulation of specific oncogenic pathways (Ras and Myc) in the TTF-1/NKX2-8 co-activated cohort.
In vitro experiments demonstrated the ability of a Ras pathway-specific therapy to inhibit tumor cell growth in TTF-1/NKX-2 activated cells, thus, suggesting that modulation of the Ras pathway is a rational strategy to targeted therapy in high risk NSCLC patients with co-activation of specific lung developmental pathways.
Keywords: Transcription factor expression analysis
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| Overall design |
Six controls and six replicates of each transcription factor (TTF1, NKX2-8, PAX9) were prepared and analyzed.
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| Contributor(s) |
Hsu DS, Acharya CR, Riedel RF, Redman R, Garman K, Balakumaran BS, Anguiano A, Mukherjee S, Barry W, Ginsburg G, Febbo PG, Nevins JR, Powers S, Mu D, Potti A |
| Citation(s) |
19279207 |
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| Submission date |
Oct 02, 2007 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Chaitanya R Acharya |
| E-mail(s) |
[email protected]
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| Phone |
919-681-8350
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| Organization name |
Duke University
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| Department |
Dept. of Surgery
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| Lab |
Lyerly Lab
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| Street address |
203 Research Drive,Medical Sciences Research Building, Suite 433
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| City |
Durham |
| State/province |
NC |
| ZIP/Postal code |
27710 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA102799 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE9212_RAW.tar |
136.9 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
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