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Total 64 results found since Jan 2013.

Abstract 4999: Signaling-associated complexes to define targetable vulnerabilities in lung cancer
Lung cancer is the leading cause of cancer related death in the U.S. Despite successes targeting tyrosine kinase drivers such as EGFR and EML4-ALK, identification of patients who will benefit from emerging targeted therapy regimens remains a challenge. This is exemplified by the disappointing results in the recent Phase III evaluation of ornatuzumab in combination with erlotinib in advanced non-small cell lung cancer (NCT01456324), targeting both MET and EGFR in biomarker-defined patient populations. We have previously shown that proximity ligation assay (PLA) technology can be harnessed to evaluate EGFR pathway activation...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Smith, M., Licata, T., Bai, Y., Zhang, G., Vuaroqueaux, V., Fiebig, H.-H., Haura, E. B. Tags: Molecular and Cellular Biology Source Type: research

Abstract 487: Whole genome screen to identify genes targeting MYCN-driven embryonal tumors
MYCN is a driver of neuroblastoma (NB) tumorigenesis and is over-expressed in a number of tumors of embryonal origin, including rhabdomyosarcoma, medulloblastoma and diffuse intrinsic pontine gliomas. We sought to identify regulators of MYCN transcription by performing a whole genome screen (WGS) for regulators of MYCN promoter activity using a NB cell model. A plasmid containing the MYCN promoter (1.3kb upstream of MYCN TSS) fused to luciferase and stably integrated into the genome of NGP NB cells was the readout system. NGP-MYCNpluc, was selected based on MYCN luciferase activity inhibition by ATRA and HDAC inhibitors to...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Thiele, C. J., Liu, Z., Veschi, V., Buehler, E., Martin, S. Tags: Tumor Biology Source Type: research

Abstract 3309: Co-inhibition of ALK and EGFR and/or c-MET on cell growth and response to radiation in ALK-positive NSCLC cells
ALK (anaplastic lymphoma kinase), EGFR (epidermal growth factor receptor) and c-MET are molecular drivers for a subset of non-small cell lung cancers (NSCLC). Approximately 4-7% of NSCLCs carry the EML4-ALK chromosomal rearrangement. We identified overexpression of EGFR and c-MET in EML4-ALK-positive NSCLC cell lines H3122 and H2228. ALK, EGFR, and c-MET may function cooperatively to modulate tumor growth, stress response, and survival in EML4-ALK-positive cells and co-inhibition may favorably impact tumor control. We therefore investigated the effects of co-inhibition of ALK and EGFR or c-MET on cell survival and response...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Li, C., Huang, S., Ma, F., Armstrong, E. A., Francis, D., Werner, L., Harari, P. M. Tags: Tumor Biology Source Type: research

Abstract 2558: The mechanistic study on the effect of platinum-based chemotherapy efficacy imposed by EGFR-TKI regulated ERCC1 in non-small cell lung cancer (NSCLC)
Platinum-based chemotherapy is conventionally the first line treatment for EGFR wild type patients while EGFR-TKI is the standard for patients with mutation. Subgroup biomarker studies conducted in FASTACT-2 (Wu et al Lancet Oncology 2013) indicated that patients with positive ERCC1 attained longer overall survival and progression free survival under intercalated chemotherapy and EGFR-TKI, in comparison with solely chemotherapy. EGFR-TKI is postulated to down-regulate ERCC1 expression in EGFR wild type NSCLC cells, hence enhancing the Chemo efficacy. The study aims to investigate the missing link between EGFR and ERCC1 in ...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Cheong, H. T., Hui, C. W. C., Xu, F., Mok, T. S. K., Wong, C. H. Tags: Experimental and Molecular Therapeutics Source Type: research

Abstract 3576: Rictor alterations elicit non-canonical signaling mechanisms contributing to tumorigenicity and therapeutic resistance in non-small cell lung cancer (NSCLC)
Conclusion: Rictor alterations may define a new molecular NSCLC subtype with distinct biology that expose unique avenues for therapeutic intervention. Ongoing studies are underway to explore specific therapeutic strategies, non-canonical signaling and Rictor mutations.Supported by: NHI-NCI CA155196 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3576. doi:10.1158/1538-7445.AM2015-3576
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Ruder, D., Papadimitrakopoulou, V., Shien, K., Kalhor, N., Lee, J. J., Hong, W. K., Tang, X., Girard, L., Minna, J. D., Diao, L., Wang, J., Hanson, N. E., Sun, J., Miller, V., Frampton, G., Herbst, R. S., Wistuba, I. I., Izzo, J. G. Tags: Experimental and Molecular Therapeutics Source Type: research

Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells.
Abstract Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H+ ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilo...
Source: Toxicology and Applied Pharmacology - May 14, 2015 Category: Toxicology Authors: Jin HO, Hong SE, Kim CS, Park JA, Kim JH, Kim JY, Kim B, Chang YH, Hong SI, Hong YJ, Park IC, Lee JK Tags: Toxicol Appl Pharmacol Source Type: research

Neurokinin-1 activation affects EGFR related signal transduction in triple negative breast cancer.
Abstract Breast cancers bear overexpression of neurokinin-1 (NK-1). The aim of this study was to investigate the relationship between NK-1 and EGFR in triple negative breast cancers (TNBCs). Immunohistochemistry was performed to investigate NK-1 and EGFR expressions in TNBCs. [Sar(9),Met(O2)(11)] substance P (SMSP) was used to activate NK-1 in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. L-733060 and siRNA against NK-1 was used to inhibit NK-1. The in vitro regulatory effect of NK-1 was determined using CCK-8 proliferation assay. The effects of NK-1 activation and inhibition on EGFR and its downstreaming pathwa...
Source: Cellular Signalling - March 25, 2015 Category: Cytology Authors: Wang JG, Juan Y, Hu JL, Yang WL, Ren H, Ding D, Zhang L, Liu XP Tags: Cell Signal Source Type: research

Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest.
CONCLUSION: For NSCLC cells increase in radiosensitivity by EGFR inhibition results from enhanced G1-arrest. However, this effect does not lead to improved tumor control because cells can be released from this arrest by re-stimulation. PMID: 25796091 [PubMed - as supplied by publisher]
Source: Radiotherapy and Oncology : journal of the European Society for Therapeutic Radiology and Oncology - March 18, 2015 Category: Radiology Authors: Kriegs M, Gurtner K, Can Y, Brammer I, Rieckmann T, Oertel R, Wysocki M, Dorniok F, Gal A, Grob TJ, Laban S, Kasten-Pisula U, Petersen C, Baumann M, Krause M, Dikomey E Tags: Radiother Oncol Source Type: research

Low expression of the E3 Ubiquitin Ligase CBL Confers Chemoresistance in Human Pancreatic Cancer and is Targeted by Epidermal Growth Factor Receptor Inhibition.
Conclusions: Low CBL causes chemoresistance in PDAC via stress-induced EGFR activation that can be effectively abrogated by EGFR inhibition. These results suggest that dysregulation of ubiquitination is a key mechanism of EGFR hyperactivation in PDAC and that low CBL may define PDAC tumors likely to respond to erlotinib treatment. PMID: 25348515 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - October 27, 2014 Category: Cancer & Oncology Authors: Kadera BE, Toste PA, Wu N, Li L, Nguyen AH, Dawson DW, Donahue TR Tags: Clin Cancer Res Source Type: research

Abstract 856: Combination of crizotinib and radiation in the treatment of ALK-positive and cetuximab-resistant lung cancer
We examined the effect of crizotinib in combination with radiation on ALK signaling, cell proliferation, cell cycle distribution and radiosensitivity in ALK-positive NSCLC cell lines H3122 and H2228 in vitro. We also examined the in-vivo effects of crizotinib in combination with radiation in H3122 and H2228 xenograft models. Crizotinib blocked phosphorylation of ALK and its downstream effectors and inhibited cell proliferation in a dose-dependent manner. The combination of crizotinib and radiation resulted in increased inhibition of cell growth. Although cells were sensitized to radiation by crizotinib, molecular knockdown...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Li, C., Huang, S., Walters, N., Armstrong, E. A., Harari, P. M. Tags: Clinical Research (Excluding Clinical Trials) Source Type: research

Abstract 5323: Integrated computational cell-line modeling of drug sensitivity and high-throughput siRNA screening reveals novel molecular biomarkers for conventional chemotherapy
Conclusions: We present an integrated approach that combines a novel Bayesian multi-task learning model with high-throughput siRNA screens. Our approach aims to uncover sets of important aberrations and allows for the subtyping of drugs based on similarities in targets and mechanisms of action. We integrate our results with high-throughput RNAi experiments to identify synthetic lethal events in specific therapeutic context. Citation Format: Olga H. Nikolova, Mehmet Gönen, Rodrigo Dienstmann, In Sock Jang, Russell Moser, Silvia Cermelli, Chang Xu, Ryan M. Mitchell, Eduardo Mendez, Carla Grandori, Christopher Kemp, Stephen ...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Nikolova, O. H., Gonen, M., Dienstmann, R., Jang, I. S., Moser, R., Cermelli, S., Xu, C., Mitchell, R. M., Mendez, E., Grandori, C., Kemp, C., Friend, S., Guinney, J., Margolin, A. Tags: Molecular and Cellular Biology Source Type: research

Abstract 2762: Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show favorable effects in EGFR mutant lung cancer. However, responders eventually develop acquired resistance almost without exception, and secondary T790M mutations in EGFR account for approximately 50% of the acquired resistance. Recent studies indicated that EGFR mutant lung cancer cells are dependent on EGFR/Akt signaling for survival even after acquired T790M secondary mutation. Akt kinase-interacting protein1 (Aki1) is a scaffold protein that binds to wild-type EGFR after EGF ligand stimulation, maintains signa...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Yamada, T., Carbone, D. P., Takeuchi, S., Fujita, N., Yano, S. Tags: Experimental and Molecular Therapeutics Source Type: research

Abstract 2269: Combination of erlotinib and epigallocatechin-3-gallate induces apoptosis of squamous cell carcinoma of the head and neck through posttranslational regulation of Bim and Bcl-2
Conclusion: Our results strongly suggest that the combination of erlotinib and EGCG induces apoptosis of SCCHN cells by regulating Bim and Bcl-2 at the post-translational level. Currently, a clinical trial is underway at Winship Cancer Institute of Emory University to inhibit or reverse the progression of oral premalignant lesions using this combination. (This study is supported by R03CA159369, P50CA128613 and Robbins Scholar Award of Winship Cancer Institute). Citation Format: Abedul Haque, Mohammad A. Rahman, Zhuo G. Chen, Dong M. Shin, A.R.M. Ruhul Amin. Combination of erlotinib and epigallocatechin-3-gallate induces ap...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Haque, A., Rahman, M. A., Chen, Z. G., Shin, D. M., Amin, A. R. M. R. Tags: Molecular and Cellular Biology Source Type: research

Abstract 774: EGFR-regulated RGS expression contributes to paclitaxel resistance in human lung cancer cells
Lung cancer is one of the main causes of cancer-related death worldwide, and the 5-year survival of lung cancer is less than 20%. Paclitaxel is a widely used chemotherapeutic agent to treat a variety of cancers, but its therapeutic efficacy tends to be limited due to the development of drug resistance, raising the need to understand the molecular mechanisms underlying paclitaxel resistance. In the current study, we investigated the mechanisms of paclitaxel resistance in non-small cell lung cancers (NSCLCs). First, we established paclitaxel-resistant NSCLC cell lines, including H460 TxR and SK-MES TxR, by pulse- or prolonge...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Park, S.-H., Sung, M.-A., Lee, H.-Y. Tags: Experimental and Molecular Therapeutics Source Type: research

Effect of simvastatin on the resistance to EGFR tyrosine kinase inhibitors in a non-small cell lung cancer with the T790M mutation of EGFR.
This study investigated overcoming resistance to EGFR-TKI using simvastatin. We demonstrated that addition of simvastatin to gefitinib enhanced caspase-dependent apoptosis in T790M mutant NSCLC cells. Simvastatin also strongly inhibited AKT activation, leading to suppression of β-catenin activity and the expression of its targets, survivin and cyclin D1. Both insulin treatment and AKT overexpression markedly increased p-β-catenin and survivin levels, even in the presence of gefitinib and simvastatin. However, inhibition of AKT by siRNA or LY294002 treatment decreased p-β-catenin and survivin levels. To determine the rol...
Source: Experimental Cell Research - March 12, 2014 Category: Cytology Authors: Hwang KE, Kwon SJ, Kim YS, Park DS, Kim BR, Yoon KH, Jeong ET, Kim HR Tags: Exp Cell Res Source Type: research