Activating mutations in the K-ras proto-oncogene occur in 30% of lung adenocarcinomas, the most common subtype of non-small cell lung cancer (NSCLC). K-ras is a membrane-associated GTPase that activates multiple kinase pathways, several of which have transforming activity in cellular models. Which of these downstream mediators of K-ras contribute to lung tumorigenesis has not been fully elucidated. Moreover, no effective approaches are available for the treatment of K-ras-mutant NSCLC. To address this problem, we investigated a mouse model (K-rasl_A1) that develops lung adenocarcinoma through somatic activation of oncogenic K-ras (G12D). We observed prominent inflammatory cells (macrophages and neutrophils), vascular endothelial cells, and bronchioalveolar stem cells (BASCs, the putative precursors of lung adenocarcinoma cells) infiltrating atypical alveolar hyperplasia (AAH) lesions and adenomas. This finding indicates that a stromal response induced by oncogenic K-ras accompanies early lung neoplasia. Our global hypothesis is that oncogenic K-ras-induced lung tumorigenesis is driven in part by a host response to the presence of transformed alveolar epithelial cells. These cells arise from BASCs and secrete chemokines that recruit inflammatory cells and endothelial cells, which, in turn, secrete chemokines and growth factors that promote BASC expansion, thereby accelerating lung tumorigenesis. We will test this hypothesis by carrying out two Specific Aims.
In Aim 1, we will use a genetic approach (loss of 3-phosphoinositide-dependent kinase [PDK-1], a PI3K-dependent kinase) to confirm our finding that pharmacologic inhibition of PI3Kdependent signaling (PX-866 or CCI-779) is sufficient to block lung tumorigenesis induced by oncogenic Kras, and we will examine whether agents that target intra-tumoral endothelial cells (neutralizing CXCR-2 antibody) and inflammatory cells (CCI-779) have cooperative anti-tumor effects.
In Aim 2, we will translate our findings in KrasLAI mice to the clinic by examining whether NSCLC patients with K-ras-mutant tumors have increased serum concentrations of CXCR2 ligands, which thereby mobilize CXCR2pos blood cells into the circulation. We have established the ability to detect by flow cytometric analysis circulating endothelial cell and CXCR2pos monocytic populations, which we will examine as biomarkers of response to treatment with a neutralizing anti-CXCR2 antibody in a Phase I clinical trial in cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of Texas Sw Medical Center Dallas
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Goodwin, Justin; Neugent, Michael L; Lee, Shin Yup et al. (2017) The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition. Nat Commun 8:15503
Cao, Xiaobo; Zhao, Yang; Wang, Jing et al. (2017) TUSC2 downregulates PD-L1 expression in non-small cell lung cancer (NSCLC). Oncotarget 8:107621-107629
Zhou, Fei; Wang, Yanru; Liu, Hongliang et al. (2017) Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs. Mol Carcinog 56:1227-1238
Tagal, Vural; Wei, Shuguang; Zhang, Wei et al. (2017) SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers. Nat Commun 8:14098
Jafri, Mohammad Alam; Al-Qahtani, Mohammed Hussein; Shay, Jerry William (2017) Role of miRNAs in human cancer metastasis: Implications for therapeutic intervention. Semin Cancer Biol 44:117-131
Cardnell, Robert J; Li, Lerong; Sen, Triparna et al. (2017) Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies. Oncotarget 8:73419-73432
Faubert, Brandon; Li, Kevin Y; Cai, Ling et al. (2017) Lactate Metabolism in Human Lung Tumors. Cell 171:358-371.e9
Rabellino, Andrea; Andreani, Cristina; Scaglioni, Pier Paolo (2017) The Role of PIAS SUMO E3-Ligases in Cancer. Cancer Res 77:1542-1547
Fu, Rong; Wang, Pei; Ma, Weiping et al. (2017) A statistical method for detecting differentially expressed SNVs based on next-generation RNA-seq data. Biometrics 73:42-51
Quek, Kelly; Li, Jun; Estecio, Marcos et al. (2017) DNA methylation intratumor heterogeneity in localized lung adenocarcinomas. Oncotarget 8:21994-22002

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