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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA070907-14
Application #
8290536
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2011-06-27
Budget End
2012-04-30
Support Year
14
Fiscal Year
2011
Total Cost
$238,299
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Guo, Hou-Fu; Tsai, Chi-Lin; Terajima, Masahiko et al. (2018) Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+-binding. Nat Commun 9:512
Meraz, Ismail M; Majidi, Mourad; Cao, Xiaobo et al. (2018) TUSC2 Immunogene Therapy Synergizes with Anti-PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic Kras-Mutant Mouse Lung Cancer Models. Cancer Immunol Res 6:163-177
Zhang, Liren; Lin, Jing; Ye, Yuanqing et al. (2018) Serum MicroRNA-150 Predicts Prognosis for Early-Stage Non-Small Cell Lung Cancer and Promotes Tumor Cell Proliferation by Targeting Tumor Suppressor Gene SRCIN1. Clin Pharmacol Ther 103:1061-1073
Bayo, Juan; Tran, Tram Anh; Wang, Lei et al. (2018) Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks. Cell Rep 25:1040-1050.e5
Ludlow, Andrew T; Wong, Mandy Sze; Robin, Jerome D et al. (2018) NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer. Nat Commun 9:3112
Chen, Limo; Diao, Lixia; Yang, Yongbin et al. (2018) CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade. Cancer Discov 8:1156-1175
Mender, Ilgen; LaRanger, Ryan; Luitel, Krishna et al. (2018) Telomerase-Mediated Strategy for Overcoming Non-Small Cell Lung Cancer Targeted Therapy and Chemotherapy Resistance. Neoplasia 20:826-837
Gong, Ke; Guo, Gao; Gerber, David E et al. (2018) TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. J Clin Invest 128:2500-2518
Wang, Jacqueline F; Pu, Xingxiang; Zhang, Xiaoshan et al. (2018) Variants with a low allele frequency detected in genomic DNA affect the accuracy of mutation detection in cell-free DNA by next-generation sequencing. Cancer 124:1061-1069
Rashdan, Sawsan; Minna, John D; Gerber, David E (2018) Diagnosis and management of pulmonary toxicity associated with cancer immunotherapy. Lancet Respir Med 6:472-478

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