Discovery of Small Molecule NSC290956 as a Therapeutic Agent for KRas Mutant Non-Small-Cell Lung Cancer

HRas-GTP has a transient intermediate state with a “non-signaling open conformation” in GTP hydrolysis and nucleotide exchange. Due to the same hydrolysis process and the structural homology, it can be speculated that the active KRas adopts the same characteristics with the “open conformation.” This implies that agents locking this “open conformation” may theoretically block KRas-dependent signaling. Applying our specificity-affinity drug screening approach, NSC290956 was chosen by high affinity and specificity interaction with the “open conformation” structure HRasG60A-GppNp. In mutant KRas-driven non-small-cell lung cancer (NSCLC) model system, NSC290956 effectively suppresses the KRas-GTP state and gives pharmacological KRas inhibition with concomitant blockages of both the MAPK-ERK and AKT-mTOR pathways. The dual inhibitory effects lead to the metabolic phenotype switching from glycolysis to mitochondrial metabolism, which promotes the cancer cell death. In the xenograft model, NSC290956 significantly reduces H358 tumor growth in nude mice by mechanisms similar to those observed in the cells. Our work indicates that NSC290956 can be a promising agent for the mutant KRas-driven NSCLC therapy.

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Nicotine Induces Resistance to Erlotinib Therapy in Non-Small-Cell Lung Cancer Cells Treated with Serum from Human Patients

Cancers ◽

10.3390/cancers11030282 ◽

2019 ◽

Vol 11 (3) ◽

pp. 282 ◽

Cited By ~ 3

Author(s):

Tatsuya Imabayashi ◽

Junji Uchino ◽

Hisayuki Osoreda ◽

Keiko Tanimura ◽

Yusuke Chihara ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Cell Lung Cancer ◽

Xenograft Model ◽

Cancer Cell Lines ◽

Small Cell ◽

Small Cell Lung ◽

Erlotinib Therapy

Previously, we reported that nicotine reduces erlotinib sensitivity in a xenograft model of PC9, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitive non-small-cell lung cancer cell line. The present study examined whether smoking induces erlotinib resistance in vitro. We assessed resistance to EGFR-TKIs by treating cancer cell lines with erlotinib, afatinib, or osimertinib, and serum collected from smokers within 30 min of smoking and that from a non-smoker as a control. We also assessed erlotinib resistance by treating PC9 cells exposed to serum from a smoker or a non-smoker, or serum from an erlotinib user. Treatment of the cancer cell lines with serum from smokers induced significant erlotinib resistance, compared with the control (p < 0.05). Furthermore, serum samples with a high concentration of cotinine (a nicotine exposure indicator) demonstrated stronger erlotinib resistance than those with low concentrations. Similar to the observations with erlotinib treatment of cell lines, the analysis of serum from erlotinib users revealed that smokers demonstrated significantly reduced sensitivity to erlotinib (p < 0.001). In conclusion, our present results support the hypothesis that smoking contributes to resistance to erlotinib therapy in non-small-cell lung cancer.

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Induction of Acquired Resistance towards EGFR Inhibitor Gefitinib in a Patient-Derived Xenograft Model of Non-Small Cell Lung Cancer and Subsequent Molecular Characterization

Cells ◽

10.3390/cells8070740 ◽

2019 ◽

Vol 8 (7) ◽

pp. 740 ◽

Cited By ~ 5

Author(s):

Julia Schueler ◽

Cordula Tschuch ◽

Kerstin Klingner ◽

Daniel Bug ◽

Anne-Lise Peille ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Xenograft Model ◽

Small Cell ◽

Small Cell Lung ◽

Protein Ratio ◽

Patient Derived Xenograft ◽

Resistant Lines

In up to 30% of non-small cell lung cancer (NSCLC) patients, the oncogenic driver of tumor growth is a constitutively activated epidermal growth factor receptor (EGFR). Although these patients gain great benefit from treatment with EGFR tyrosine kinase inhibitors, the development of resistance is inevitable. To model the emergence of drug resistance, an EGFR-driven, patient-derived xenograft (PDX) NSCLC model was treated continuously with Gefitinib in vivo. Over a period of more than three months, three separate clones developed and were subsequently analyzed: Whole exome sequencing and reverse phase protein arrays (RPPAs) were performed to identify the mechanism of resistance. In total, 13 genes were identified, which were mutated in all three resistant lines. Amongst them the mutations in NOMO2, ARHGEF5 and SMTNL2 were predicted as deleterious. The 53 mutated genes specific for at least two of the resistant lines were mainly involved in cell cycle activities or the Fanconi anemia pathway. On a protein level, total EGFR, total Axl, phospho-NFκB, and phospho-Stat1 were upregulated. Stat1, Stat3, MEK1/2, and NFκB displayed enhanced activation in the resistant clones determined by the phosphorylated vs. total protein ratio. In summary, we developed an NSCLC PDX line modelling possible escape mechanism under EGFR treatment. We identified three genes that have not been described before to be involved in an acquired EGFR resistance. Further functional studies are needed to decipher the underlying pathway regulation.

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ZEB1-AS1 is associated with poor prognosis in non-small-cell lung cancer and influences cell migration and apoptosis by repressing ID1

Clinical Science ◽

10.1042/cs20180983 ◽

2019 ◽

Vol 133 (2) ◽

pp. 381-392 ◽

Cited By ~ 4

Author(s):

Jianjun Jin ◽

Huanqin Wang ◽

Jiming Si ◽

Ran Ni ◽

Yuanhua Liu ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Poor Prognosis ◽

Xenograft Model ◽

Vital Role ◽

Small Cell ◽

Migration And Invasion ◽

Small Cell Lung ◽

Advanced Tumor

Abstract Long non-coding RNAs (lncRNAs) have been reported to play a vital role in non-small-cell lung cancer (NSCLC). ZEB1-AS1 overexpression predicts a poor prognosis in osteosarcoma and colorectal cancers. In the current study, we determined the clinical significance and prognostic value of ZEB1-AS1 in patients with NSCLC. The expression of ZEB1-AS1 and inhibitor of differentiation-1 (ID1) was measured using qRT-PCR and Western blot. Cell growth, migration, and invasion were determined using colony formation assays, Transwell assay, and flow cytometry, respectively. Tumor growth was determined with a xenograft model. ZEB1-AS1 was significantly up-regulated in NSCLC tissues compared with normal samples. ZEB1-AS1 overexpression was significantly associated with advanced tumor, lymph node, and metastases (TNM) stage and tumor size, as well as poorer overall survival. Moreover, ZEB1-AS1 knockdown inhibited NSCLC cell proliferation and migration, and promoted cell apoptosis. In addition, a chromatin immunoprecipitation assay revealed that ZEB1-AS1 interacted with STAT3, thereby repressing ID1 expression. Furthermore, rescue experiments indicated that ZEB1-AS1 functioned as an oncogene partly by repressing ID1 in NSCLC cells. Taken together, our findings indicate that ZEB1-AS1 serves as a promising therapeutic target to predict the prognosis of NSCLC.

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Abstract 5385: Thymoquinone(TQ) and cisplatin(CDDP) in a non-small cell lung cancer (NSCLC) xenograft model

10.1158/1538-7445.am10-5385 ◽

2010 ◽

Author(s):

Syed H. Jafri ◽

Molly Boyd ◽

Shakeela Bahadur ◽

Jonathan Glass ◽

Runhua Shi ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Xenograft Model ◽

Small Cell ◽

Small Cell Lung

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Abstract 5045: The Hh inhibitor IPI-926 inhibits relapse of a non-small cell lung cancer xenograft model following treatment with an EGF-R targeted tyrosine kinase inhibitor

10.1158/1538-7445.am10-5045 ◽

2010 ◽

Author(s):

Everton Mandley ◽

Kerry White ◽

Kerrie Faia ◽

Veronica Travaglione ◽

Margaret Read ◽

...

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Tyrosine Kinase Inhibitor ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Xenograft Model ◽

Small Cell ◽

Small Cell Lung ◽

Model Following

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LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

Cancers ◽

10.3390/cancers11050705 ◽

2019 ◽

Vol 11 (5) ◽

pp. 705 ◽

Cited By ~ 10

Author(s):

Cédric Zeltz ◽

Elena Pasko ◽

Thomas R. Cox ◽

Roya Navab ◽

Ming-Sound Tsao

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Xenograft Model ◽

Tumor Stroma ◽

Small Cell ◽

Matrix Remodeling ◽

Small Cell Lung

Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.

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Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non–small cell lung cancer

Journal of Experimental Medicine ◽

10.1084/jem.20180870 ◽

2019 ◽

Vol 216 (4) ◽

pp. 982-1000 ◽

Cited By ~ 44

Author(s):

Bo Gong ◽

Kazuma Kiyotani ◽

Seiji Sakata ◽

Seiji Nagano ◽

Shun Kumehara ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Transmembrane Domain ◽

Xenograft Model ◽

Immune Checkpoint Blockade ◽

Small Cell ◽

Small Cell Lung ◽

Antibody Treatment ◽

Nsclc Patients

Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand PD-L1 often induces durable tumor responses in various cancers, including non–small cell lung cancer (NSCLC). However, therapeutic resistance is increasingly observed, and the mechanisms underlying anti–PD-L1 (aPD-L1) antibody treatment have not been clarified yet. Here, we identified two unique secreted PD-L1 splicing variants, which lacked the transmembrane domain, from aPD-L1–resistant NSCLC patients. These secreted PD-L1 variants worked as “decoys” of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8 T cells and cancer cells. Importantly, mixing only 1% MC38 cells with secreted PD-L1 variants and 99% of cells that expressed wild-type PD-L1 induced resistance to PD-L1 blockade in the MC38 syngeneic xenograft model. Moreover, anti–PD-1 (aPD-1) antibody treatment overcame the resistance mediated by the secreted PD-L1 variants. Collectively, our results elucidated a novel resistant mechanism of PD-L1 blockade antibody mediated by secreted PD-L1 variants.

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