An Integrated Molecular Analysis of Lung Adenocarcinomas Identifies Potential Therapeutic Targets among TTF1-Negative Tumors, Including DNA Repair Proteins and Nrf2

Abstract

Purpose Thyroid transcription factor-1 (TTF1) immunohistochemistry (IHC) is used clinically to differentiate primary lung adenocarcinomas (LUAD) from squamous lung cancers and metastatic adenocarcinomas from other primary sites. However, a subset of LUAD (15-20%) does not express TTF1 and TTF1-negative patients have worse clinical outcomes. As there are no established targeted agents with activity in TTF1-negative LUAD, we performed an integrated molecular analysis to identify potential therapeutic targets. Experimental Design Using two clinical LUAD cohorts (274 tumors), one from our institution (PROSPECT) and the TCGA, we interrogated proteomic profiles (by reverse-phase protein array (RPPA)), gene expression, and mutational data. Drug response data from 74 cell lines were used to validate potential therapeutic agents. Results Strong correlations were observed between TTF1 IHC and TTF1 measurements by RPPA (Rho=0.57, p<0.001) and gene expression (NKX2-1, Rho=0.61, p<0.001). Established driver mutations (e.g. BRAF and EGFR) were associated with high TTF1 expression. In contrast, TTF1-negative LUAD had a higher frequency of inactivating KEAP1 mutations (p=0.001). Proteomic profiling identified increased expression of DNA repair proteins (e.g., Chk1 and the DNA repair score) and suppressed PI3K/MAPK signaling among TTF1-negative tumors, with differences in total proteins confirmed at the mRNA level. Cell line analysis showed drugs targeting DNA repair to be more active in TTF1-low cell lines. Conclusions Combined genomic and proteomic analyses demonstrated infrequent alteration of validated lung cancer targets (including the absence of BRAF mutations in TTF1-negative LUAD), but identified novel potential targets for TTF1-negative LUAD includingKEAP1/Nrf2 and DNA repair pathways.

Targeted Expression of miR-7 Operated by TTF-1 Promoter Inhibited the Growth of Human Lung Cancer through the NDUFA4 Pathway

“…To verify this phenomenon, we also detected the expression of TTF-1 in these cancer cells, which also valuably reflected the intrinsic activity of TTF-1 promoter. Consistently, we found that the expression level of TTF-1 was also higher in lung cancer cells than that in other cancer cells, which was consistent with previous finding that TTF-1 was dominantly expressed in lung cancer cells, but not other types of cancer cells 24, 25, 26…”

IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras–Mutant Lung Cancer

“…This cohort was obtained from the Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (PROSPECT) study, developed in 2006 at M.D. Anderson Cancer Center (14). Clinical characteristics of these patients are presented in Table 1.…”

AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers

“…The MDACC PROSPECT cohort (Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax) of surgically resected NSCLC tumors was collected and profiled by reverse phase protein array (RPPA) as previously described (22). RPPA data from tumor cohorts for lung adenocarcinoma and lung squamous patients from The Cancer Genome Atlas (TCGA) were profiled similarly using previously established methods (8, 23-25).…”