PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors

Slides:

Advertisements

Similar presentations

Manish R. Patel, DO, Blake A

Advertisements

Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation

Inducible EGFR T790M-Mediated Gefitinib Resistance in Non-small Cell Lung Cancer Cells Does Not Modulate Sensitivity to PI103 Provoked Autophagy Flavia.

Alpha-Actinin 4 Is Associated with Cancer Cell Motility and Is a Potential Biomarker in Non–Small Cell Lung Cancer Ming-Chuan Wang, PhD, Ying-Hua Chang,

Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.

Cantharidin Inhibits the Growth of Triple-Negative Breast Cancer Cells by Suppressing Autophagy and Inducing Apoptosis in Vitro and in.

The Autophagy Inhibitor Chloroquine Overcomes the Innate Resistance of Wild-Type EGFR Non-Small-Cell Lung Cancer Cells to Erlotinib Yiyu Zou, PhD, Yi-He.

Fig. 4. TR3-dependent induction of ATF3 by DIM-C-pPhOCH 3 in human pancreatic cancer cells. ( A ) Induction of ATF3 by DIM-C-pPhOCH 3

Cell Physiol Biochem 2017;44:1867– DOI: /

Silencing NKD2 by Promoter Region Hypermethylation Promotes Esophageal Cancer Progression by Activating Wnt Signaling Baoping Cao, MD, PhD, Weili Yang,

PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors

Antitumor Efficacy of the Anti-Interleukin-6 (IL-6) Antibody Siltuximab in Mouse Xenograft Models of Lung Cancer Lanxi Song, MS, Matthew A. Smith, PhD,

Dual Inhibition of PI3K/AKT and MEK/ERK Pathways Induces Synergistic Antitumor Effects in Diffuse Intrinsic Pontine Glioma Cells Y. Linda Wu, Uday Bhanu.

Cell Surface CD74–MIF Interactions Drive Melanoma Survival in Response to Interferon-γ Keiji Tanese, Yuuri Hashimoto, Zuzana Berkova, Yuling Wang, Felipe.

Yunguang Sun, PhD, Luigi Moretti, MD, Nicholas J

Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR- Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients.

Integrin αvβ6 Promotes Lung Cancer Proliferation and Metastasis through Upregulation of IL-8–Mediated MAPK/ERK Signaling Pengwei Yan, Huanfeng Zhu, Li.

Antitumor Effect of AZD4547 in a Fibroblast Growth Factor Receptor 2–Amplified Gastric Cancer Patient–Derived Cell Model Jiryeon Jang, Hee Kyung Kim,

Manish R. Patel, DO, Blake A

Vemurafenib Induces Senescence Features in Melanoma Cells

Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI- 258) and its Therapeutic Implications Shalini S. Yadav, Jinyi.

MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values Geun Dong Lee, MD, PhD, Seung Eun Lee, MD,

Up-Regulation of RFC3 Promotes Triple Negative Breast Cancer Metastasis and is Associated With Poor Prognosis Via EMT Zhen-Yu He, San-Gang Wu, Fang Peng,

MET Tyrosine Kinase Inhibitor Crizotinib (PF ) Shows Differential Antitumor Effects in Non-small Cell Lung Cancer According to MET Alterations

Droxinostat, a Histone Deacetylase Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cell Lines via Activation of the Mitochondrial Pathway and.

E1B-55 kDa-Defective Adenoviruses Activate p53 in Mesothelioma and Enhance Cytotoxicity of Anticancer Agents Makako Yamanaka, MD, Yuji Tada, MD, PhD,

IFN-γ Induces Gastric Cancer Cell Proliferation and Metastasis Through Upregulation of Integrin β3-Mediated NF-κB Signaling Yuan-Hua Xu, Zheng-Li Li,

Sarah A. Best, Amy N. Nwaobasi, Chrysalyne D. Schmults, Matthew R

Bertrand Poussier, MD, Alfredo C

Sarah A. Best, Amy N. Nwaobasi, Chrysalyne D. Schmults, Matthew R

The Zinc Ionophore PCI-5002 Radiosensitizes Non-small Cell Lung Cancer Cells by Enhancing Autophagic Cell Death Kwang Woon Kim, PhD, Christina K. Speirs,

Continual Exposure to Cigarette Smoke Extracts Induces Tumor-Like Transformation of Human Nontumor Bronchial Epithelial Cells in a Microfluidic Chip

Volume 137, Issue 5, Pages (May 2009)

Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.

The Unique Characteristics of MET Exon 14 Mutation in Chinese Patients with NSCLC Si-Yang Liu, MD, Lan-Ying Gou, MD, An-Na Li, MD, Na-Na Lou, MMed, Hong-Fei.

Alpha-Actinin 4 Is Associated with Cancer Cell Motility and Is a Potential Biomarker in Non–Small Cell Lung Cancer Ming-Chuan Wang, PhD, Ying-Hua Chang,

Pulmonary Fibroblasts Induce Epithelial Mesenchymal Transition and Some Characteristics of Stem Cells in Non-Small Cell Lung Cancer Yasushi Shintani,

Yes-Associated Protein Contributes to the Development of Human Cutaneous Squamous Cell Carcinoma via Activation of RAS Jinjing Jia, Changji Li, Suju.

Volume 6, Issue 1, Pages (January 2014)

Inducible EGFR T790M-Mediated Gefitinib Resistance in Non-small Cell Lung Cancer Cells Does Not Modulate Sensitivity to PI103 Provoked Autophagy Flavia.

Combining the Multitargeted Tyrosine Kinase Inhibitor Vandetanib with the Antiestrogen Fulvestrant Enhances Its Antitumor Effect in Non-small Cell Lung.

The Autophagy Inhibitor Chloroquine Overcomes the Innate Resistance of Wild-Type EGFR Non-Small-Cell Lung Cancer Cells to Erlotinib Yiyu Zou, PhD, Yi-He.

Volume 132, Issue 7, Pages (June 2007)

Combination of Gefitinib and Pemetrexed Prevents the Acquisition of TKI Resistance in NSCLC Cell Lines Carrying EGFR-Activating Mutation Silvia La Monica,

Spleen Tyrosine Kinase Mediates EGFR Signaling to Regulate Keratinocyte Terminal Differentiation Nan-Lin Wu, Duen-Yi Huang, Li-Fang Wang, Reiji Kannagi,

Hsp90 Inhibition Overcomes HGF-Triggering Resistance to EGFR-TKIs in EGFR-Mutant Lung Cancer by Decreasing Client Protein Expression and Angiogenesis

Inhibiting MDM2-p53 Interaction Suppresses Tumor Growth in Patient-Derived Non– Small Cell Lung Cancer Xenograft Models Josephine Hai, PhD, Shingo Sakashita,

Volume 141, Issue 6, Pages e5 (December 2011)

AT-101, a Pan-Bcl-2 Inhibitor, Leads to Radiosensitization of Non-small Cell Lung Cancer Luigi Moretti, MD, Bo Li, MD, Kwang Woon Kim, PhD, Heidi Chen,

Interleukin-22 Is Frequently Expressed in Small- and Large-Cell Lung Cancer and Promotes Growth in Chemotherapy-Resistant Cancer Cells Sebastian Kobold,

c-Jun Promotes whereas JunB Inhibits Epidermal Neoplasia

MicroRNA-101 Exerts Tumor-Suppressive Functions in Non-small Cell Lung Cancer through Directly Targeting Enhancer of Zeste Homolog 2 Ji-guang Zhang,

PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non–Small Cell Lung Cancer Seiichi Ikeda, MSc, Tatsuro Okamoto, MD,

CCN1, a Pro-Inflammatory Factor, Aggravates Psoriasis Skin Lesions by Promoting Keratinocyte Activation Yue Sun, Jie Zhang, Zhou Zhou, Pinru Wu, Rongfen.

Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells Yangling Li, Miao Xian, Bo Yang, Meidan.

Dasatinib, a small molecule inhibitor of the Src kinase, reduces the growth and activates apoptosis in pre-neoplastic Barrett's esophagus cell lines:

Volume 6, Issue 1, Pages (January 2014)

Continual Exposure to Cigarette Smoke Extracts Induces Tumor-Like Transformation of Human Nontumor Bronchial Epithelial Cells in a Microfluidic Chip

Volume 2, Issue 3, Pages (September 2002)

Volume 19, Issue 8, Pages (August 2011)

Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation

MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values Geun Dong Lee, MD, PhD, Seung Eun Lee, MD,

Green Tea Polyphenol Epigallocatechin-3-Gallate Suppresses Collagen Production and Proliferation in Keloid Fibroblasts via Inhibition of the STAT3-Signaling.

Shrimp miR-34 from Shrimp Stress Response to Virus Infection Suppresses Tumorigenesis of Breast Cancer Yalei Cui, Xiaoyuan Yang, Xiaobo Zhang Molecular.

Volume 19, Issue 10, Pages (October 2011)

Combined Small Cell Carcinoma of the Lung: Is It a Single Entity?

Curcumin Selectively Induces Apoptosis in Cutaneous T-Cell Lymphoma Cell Lines and Patients’ PBMCs: Potential Role for STAT-3 and NF-κB Signaling Chunlei.

Molecular Therapy - Nucleic Acids

Volume 3, Issue 5, Pages (May 2001)

Signal Transducer and Activator of Transcription 3 as Molecular Therapy for Non–Small- Cell Lung Cancer Cheng-Yi Wang, MD, Ting-Ting Chao, PhD, Wei-Tien.

Presentation transcript:

PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors Anna Teresa Alberobello, PhD, Yisong Wang, PhD, Frans Joseph Beerkens, BS, Fabio Conforti, MD, Justine N. McCutcheon, BS, Guanhua Rao, PhD, Mark Raffeld, MD, Jing Liu, MD, Raneen Rahhal, BS, Yu-Wen Zhang, MD, PhD, Giuseppe Giaccone, MD, PhD Journal of Thoracic Oncology Volume 11, Issue 8, Pages 1345-1356 (August 2016) DOI: 10.1016/j.jtho.2016.04.013 Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Morphological features and characterization of MP57 primary cells. (A) Photographs of MP57 morphological features at passages 16 and 30 taken under a light-inverted microscope (magnification ×40). (B) Immunofluorescence staining of thymic epithelial markers in MP57. The staining of cytokeratin clone AE1/AE3, EpCAM, E-cadherin, c-Kit, and p63 are indicated by fluorescein isothiocyanate (FITC). 4,6-Diamino-2-phenylindole (DAPI) was used for staining of nuclei. (C) Cell surface marker analysis of MP57 by flow cytometry. Cytokeratin clone AE1/AE3, EpCAM, p63, c-Kit, and E-cadherin and human fibroblast antibody were analyzed. Black histogram represents control isotypes. Journal of Thoracic Oncology 2016 11, 1345-1356DOI: (10.1016/j.jtho.2016.04.013) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Proliferative and tumorigenic activities of MP57 cells. Cell proliferation was measured by CellTiter Glo Viability assay (A) and the trypan blue dye exclusion method (B). For comparison, T1889 and IU-TAB1 cells were also examined. (C) Tumorigenicity of MP57 cells in immunocompromised athymic nude mice (n = 10). The curve represents the growth of subcutaneous tumors within the 5-week window. (D) MP57 xenograft tumors at the experimental end point (day35 after inoculation). (E) Histological comparison of MP57 xenograft tumor and the primary tumor obtained from patient autopsy. Morphological pattern of tumor cells was examined by hematoxylin and eosin (H&E) staining. The expression of cytokeratin 7 and p63 was determined by immunohistochemical staining. Abbreviation: RLU, relative luminescence units. Journal of Thoracic Oncology 2016 11, 1345-1356DOI: (10.1016/j.jtho.2016.04.013) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Identification of mutations in the genes encoding subunits of PI3K in thymic epithelial tumor samples. Sanger sequencing confirmation of mutations identified by MiSeq in (A) phosphoinositide-3-kinase regulatory subunit 2 gene (PIK3R2) in MP57 cells and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) in IU-TAB1 cells. (B) Sanger sequencing of mutations identified in PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma gene (PIK3CG), and phosphoinositide-3-kinase regulatory subunit 4 gene (PIK3R4) in three thymic epithelial tumor primary tumor samples, respectively. Arrows indicate the mutated nucleotides. Journal of Thoracic Oncology 2016 11, 1345-1356DOI: (10.1016/j.jtho.2016.04.013) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 PI3K inhibition suppressed protein kinase B (AKT) activation and reduced viability of TET cells. (A) Western blot analysis of AKT phosphorylation in MP57, IU-TAB1, and T1889 cells treated with the indicated concentration of GDC-0941 for 6 hours. As controls, total AKT and β-actin were also probed. (B) The viability of the indicated cells treated with increasing concentrations of GDC-0941 (ranging from 70 nM to 20 μM) for 72 hours, determined by CellTiter Glo Viability assay. The concentrations that inhibit 50% were calculated using the GraphPad Prism program (GraphPad Software, La Jolla, CA). The assay was performed in triplicate, and the error bars represent standard deviations. Journal of Thoracic Oncology 2016 11, 1345-1356DOI: (10.1016/j.jtho.2016.04.013) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 5 Effects of GDC-0941 on cell cycle, apoptosis, and motility of PI3K-mutated thymic epithelial cells. (A) Cell cycle analysis of MP57 and IU-TAB1 cells treated with the indicated concentrations of GDC-0941 for 72 hours, determined by flow cytometry of propidium iodide (PI) staining. DMSO treatment was used as the control. (B) Analysis of apoptosis by flow cytometry using annexin V and propidium iodide staining of the cells treated with the indicated concentrations of GDC-0941 for 72 hours. (C) Migration assay of MP57 cells treated with and without GDC-0941. Migrating cells were visualized by crystal violet staining (left), and the quantification was shown in the graph bars (right). Error bar represents standard deviation. Journal of Thoracic Oncology 2016 11, 1345-1356DOI: (10.1016/j.jtho.2016.04.013) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Supplementary Fig. 1 MP57 cells do not express vimentin and N-cadherin. Immunofluorescence staining was used to detect vimentin and N-cadherin (FITC). DAPI was used to stain the nucleus of the cells. Journal of Thoracic Oncology 2016 11, 1345-1356DOI: (10.1016/j.jtho.2016.04.013) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions