bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4661: Loss of LKB1 in NSCLC confers sensitivity to MEK inhibition by regulating activation of AKT-FOXO3 pathway
Authors: Yamada Tadaaki , Kaufman Jacob M. , Amann Joseph M. , Yano Seiji , Carbone David P. 
Published: July 2016

Abstract
The use of MEK inhibitors for non-small cell lung cancer (NSCLC) has shown little efficacy in clinical trials, even in the case of tumors with mutant KRAS where one might predict good outcomes. From these data, it is clear that the success of MEK inhibitors is going to rely on finding a biomarker that predicts sensitivity to this type of therapy. Our area of interest is finding a way to treat LKB1 mutant tumors and, surprisingly, an in silico screen of drug sensitivity data for NSCLC cell lines determined that four MEK inhibitors were among the top drugs that were significantly associated with LKB1 loss. We confirmed the effects MEK inhibition by evaluating 23 lung cancer cell lines with known LKB1 status. The results of the study showed that MEK inhibition with trametinib led to a significant reduction in cell viability in LKB1 mutant cell lines when compared to cell lines with wild type LKB1. In addition, we investigated MEK sensitivity by restoring wild-type (Wt) LKB1 in lung cancer cell lines with LKB1 loss, or by silencing LKB1 in lung cancer cell LKB1-Wt lines. Transduction of LKB1 resulted in significant MEK resistance in three of the five LKB1 add-back lines, while silencing LKB1 induced MEK sensitivity in all five LKB1-Wt lines tested. The mechanism behind these observed results appears to be through phosphorylation of AKT and its downstream target FOXO3, which are important determinants of the apoptotic response to MEK inhibition. With LKB1 transduction into mutant cell lines we see an increase in the activating phosphorylation of AKT, a protein involved in survival mechanisms, and an increase in the deactivating phosphorylation of FOXO3, a transcription factor implicated in increased levels of apoptosis. Our data suggest that the identification of LKB1 activity may be promising biomarker for the sensitivity to MEK inhibition by regulating activation of AKT-FOXO3 pathway in NSCLC.
Citation Format: Tadaaki Yamada, Jacob M. Kaufman, Joseph M. Amann, Seiji Yano, David P. Carbone. Loss of LKB1 in NSCLC confers sensitivity to MEK inhibition by regulating activation of AKT-FOXO3 pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4661.
Abstract 4664: Co-targeting HGF-cMET signaling with MEK inhibitors in metastatic uveal melanoma
Authors: Cheng Hanyin , Kageyama Ken , Purwin Timothy , Liao Connie , Terai Mizue , Sato Takami , Aplin Andrew 
Published: July 2016

Abstract
Metastatic uveal melanoma (UM) patients usually die within one year, emphasizing an urgent need to develop new treatment strategies. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in cutaneous melanoma patients but have limited efficacy in UM patients. Our previous work show that HGF-cMET signaling provides resistance to MEK inhibitors in metastatic UM cells. In this study, we further investigated the mechanisms of HGF-driven resistance to MEK inhibitors in metastatic UM cells. Cellular signaling pathway analysis was carried out to determine the role of downstream Bcl2 family members in overcoming trametinib-mediated apoptosis by HGF in metastatic UM cells. A new class of clinical grade cMET antibody and inhibitor were tested for their capacity to revert the resistance to trametinib mediated by HGF and tumor microenvironment. Selective inhibitors were utilized to determine the PI3K isoform dependency of metastatic UM cells in HGF-mediated protection against trametinib in metastatic UM cells. We demonstrate that the expression of two BH3-only family proteins, Bim-EL and Bmf, is upregulated in trametinib treated cells, but returns to basal levels upon HGF treatment in these cells. Targeting HGF-cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. PI3Kβ-sparing inhibitor GDC0032 effectively blocks HGF-induced AKT phosphorylation and HGF-mediated resistance in trametinib treated cells in growth assays. In conclusion, our data suggest that HGF promotes resistance to MEK inhibitors through modulating Bim-EL and Bmf expression in UM cells. Our data also support the notion that selectively blocking PI3K isoform activities or cMET signaling may delay the onset of resistance to MEK inhibitors provided by tumor microenvironment in metastatic uveal melanoma.
Citation Format: Hanyin Cheng, Ken Kageyama, Timothy Purwin, Connie Liao, Mizue Terai, Takami Sato, Andrew Aplin. Co-targeting HGF-cMET signaling with MEK inhibitors in metastatic uveal melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4664.
Abstract 4668: Silencing PTGER3 enhances chemotherapeutic responses
Authors: Bayraktar Emine , Rodriguez-Aguayo Cristian , Mai Junhua , Ivan Cristina , Ivan Cristina , Chavez-Reyes Arturo , Sood Anil K. , Ferrari Mauro , Shen Haifa , Lopez-Berestein Gabriel 
Published: July 2016

Abstract
Inflammation is involved in the pathogenesis of cancer and inflammatory mediators such as prostaglandins (PGs) are abundantly present in the tumor microenvironment. Prostaglandin E(2) (PGE(2))-prostaglandin E2 receptor (EP)3 (PTGER3) signaling appears critical for tumor-associated angiogenesis, tumor growth and chemoresistance. However, the precise mechanism of this phenomenon in ovarian cancer remains unknown. In this study we hypothesized that down modulation of PTGER3 regulates drug resistance through the regulation of Ras-MAPK/Erk-Est-ELK1 axis in OC cells, resulting in decreased migration, proliferation and increased apoptosis. We analyzed a PTGER3 data set of OC patients from the Cancer Genome Atlas. Furthermore, the analysis of a panel of ovarian cancer cell lines showed that PTGER3 at mRNA and protein levels were higher in cisplatin-resistant cells when compared with their cisplatin sensitive counterparts. In vitro cell viability, growth, cell-cycle progression, migration, invasion and apoptosis, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following siRNA-mediated PTGER3 silencing in cisplatin-resistant ovarian cancer cells. The experimental validation identifies PTGER3 associated with OC survival. Significant inhibition of cell growth and viability, cell-cycle arrest, and activation of apoptosis were observed upon siRNA-mediated PTGER3 suppression. Furthermore, combination treatment with MSV/DOPC-siRNA-PTGER3 and cisplatin inhibited growth of A2780-CP20 tumors, which were otherwise resistant to cisplatin treatment. These findings identify PTGER3 as a potential therapeutic target in ovarian chemo-resistant cancers expressing high levels of this oncogenic protein.
Citation Format: Emine Bayraktar, Cristian Rodriguez-Aguayo, Junhua Mai, Cristina Ivan, Cristina Ivan, Arturo Chavez-Reyes, Anil K. Sood, Mauro Ferrari, Haifa Shen, Gabriel Lopez-Berestein. Silencing PTGER3 enhances chemotherapeutic responses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4668.
Abstract 4670: Combinations of kinase siRNAs potentiates paclitaxel sensitivity in ovarian cancer
Authors: Yang Hailing , Wang Xiaoyan , Ahmed Ahmed , Iles Lakesla , Bartholomeusz Geoffrey , Lu Zhen , Bast Robert C. 
Published: July 2016

Abstract
Drug resistance imposes a major obstacle in ovarian cancer treatment. All patients with newly diagnosed ovarian cancer are treated with a combination of paclitaxel and carboplatin. While 70% of ovarian cancers respond to carboplatin, less than 50% respond to paclitaxel. Inhibition of kinases that modulate primary paclitaxel resistance, could enhance response to therapy. A Kinase siRNA library was screened in ovarian cancer cell lines to determine which kinases regulate paclitaxel sensitivity. Among 45 hits from high throughput screening, 14 target proteins (AATK, ACRBP, BMP2K, CHUK, EDN2, IKBKB, ILK, RAPGEF3, RAPGEF4, RFP, SIK2, STK24, STK39 and TBK1) regulated sensitivity to paclitaxel and were differentially expressed or overexpressed in a fraction of ovarian cancers. siRNAs against each of these kinases were tested for the ability to enhance sensitivity to paclitaxel in each of 12 ovarian cancer cell lines that reflected the heterogeneity observed in ovarian cancers including mutations of TP53, BRCA1/2, KRAS, BRAF, PI3K and PTEN. Knockdown of 10 individual genes enhanced paclitaxel sensitivity by at least two folds in different cell lines. A subscreen using combinations of these 14 kinase siRNAs in the six most responsive cell lines were carried out to select pairs of kinase siRNAs which could further potentiate paclitaxel sensitivity. IKBKB and STK39 kinase siRNAs had the greatest activity. We discovered that knockdown of IKBKB and STK39 stabilized microtubules judged by a microtubule fractionation assay and levels of acetylated and detyrosinated tubulin. IKBKB and STK39 kinase siRNAs also induced apoptosis. Double knockdown of microtubule stabilizing kinases IKBKB and STK39 resulted in greater enhancement in microtubule stability and apoptosis, leading to additive sensitization of paclitaxel. Small molecule inhibitors are available for IKBKB. As inhibition drugs become available for STK39, these observations can be translated to the clinic.
Citation Format: Hailing Yang, Xiaoyan Wang, Ahmed Ahmed, Lakesla Iles, Geoffrey Bartholomeusz, Zhen Lu, Robert C. Bast Jr.. Combinations of kinase siRNAs potentiates paclitaxel sensitivity in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4670.
Abstract 4673: A novel way to sensitize pancreatic cancer cells for gemcitabine treatment
Authors: Xie Jingwu , Gu Dongsheng , Zhang Xiaoli , Jia Yanfei , Chiorean Gabi 
Published: July 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a dismal median survival of 6 months. While combining albumin-bound paclitaxel with gemcitabine has shown clear therapeutic advantage, numerous attempts using novel targeted therapies did not yield clinical benefits. Gemcitabine is still the first-line treatment for patients with PDAC. We hypothesize that strategies to increase gemcitabine sensitivity may be effective in PDAC treatment. In this study, we report that cancer stem cell regulator Sox2 is highly induced in acquired gemcitabine resistant pancreatic cell lines, and down-regulation of Sox2 sensitizes cancer cells to gemcitabine treatment both in the cultured cells and in mouse models. Down-regulation of Gli1/2 was associated with reduced Sox2 expression, decreased expression of cancer stem cell markers. We found Gli1/2 proteins in association with a Sox2 promoter sequence with a putative Gli binding site, suggesting a direct regulation of Sox2 by Gli1/2. We further showed that down-regulation of Gli1 or Gli2 was as effective as Sox2 knockdown in sensitizing cancer cells to gemcitabine treatment. The relevance of Gli1/2-Sox2 signaling axis to PDAC was suggested by association of high Sox2 expression with poor survival in stage II PDAC patients. Taken together, our data indicate an important role of non-canonical hedgehog signaling in regulation of gemcitabine sensitivity, and down-regulation of Gli1/2 transcription factors, together with gemcitabine, may be effective in pancreatic cancer treatment.
Citation Format: Jingwu Xie, Dongsheng Gu, Xiaoli Zhang, Yanfei Jia, Gabi Chiorean. A novel way to sensitize pancreatic cancer cells for gemcitabine treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4673.
Abstract 4678: Inhibition of CDK4 sensitizes multidrug resistant ovarian cancer cells to paclitaxel by increasing apoptosis
Authors: GAO YAN , Shen Jacson , Foster Rosemary , Hornicek Francis J. , Duan Zhenfeng 
Published: July 2016

Abstract
Purpose: Overexpression of cyclin-dependent kinase (CDK) 4 has been shown in a variety of cancers and contributes to tumor cell growth and proliferation. However, the effect of inhibition of CDK4 in ovarian cancer is unknown. Here we investigated the therapeutic effect of CDK4 inhibitor, palbociclib, in combination with paclitaxel in ovarian cancer cells. Experimental Design: Cell viability was determined by MTT assay after incubating with different dosages of palbociclib and/or paclitaxel. Western blot, immunofluorescence, and Calcein AM assays were conducted to determine the potential effects and mechanisms of palbociclib in combination with paclitaxel. CDK4 siRNA was used to validate the outcome of targeting CDK4 in ovarian cancer cells. Immunohistochemistry was performed to evaluate the clinical relevance of CDK4 expression in an ovarian cancer tissue microarray. Results: The combination of palbociclib and paclitaxel significantly enhanced drug sensitivity in both Rb positive (Rb+) and Rb negative (Rb-) ovarian cancer cells. Palbociclib suppressed the phosphorylation of pRb (Ser 807-811, Ser 795, and Ser 780) in multidrug resistant SKOV3TR (Rb+) cells. When combined with paclitaxel, palbociclib induced significant apoptosis in both SKOV3TR (Rb+) and OVCAR8TR (Rb-) cells. Palbociclib also inhibited the activity of P-glycoprotein (Pgp). Additionally, transfection of CDK4 siRNA showed effective knockdown of CDK4 expression and sensitized multidrug resistant SKOV3TR and OVCAR8TR cells to paclitaxel. Furthermore, primary ovarian cancer patients with high expression of CDK4 tended to have unfavorable clinical outcomes. Conclusions: Inhibition of CDK4 either by palbociclib or by specific siRNA can increase the in vitro paclitaxel sensitivity in either Rb+ or Rb- multidrug resistant ovarian cancer cells through increased apoptosis. Therefore, CDK4 may be a promising target in the treatment of ovarian cancer.
Citation Format: YAN GAO, Jacson Shen, Rosemary Foster, Francis J. Hornicek, Zhenfeng Duan. Inhibition of CDK4 sensitizes multidrug resistant ovarian cancer cells to paclitaxel by increasing apoptosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4678.
Abstract 4680: Restoration of EGFR-TKI resistance by endocytosis inhibitor PAO in lung cancer with wild-type EGFR
Authors: Kim Boyeon , Sung Jae Sook , Kim Yeul Hong 
Published: July 2016

Abstract
Therapeutic efficacy of epithelial growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is currently limited in selected lung cancer patients who have TKI sensitive EGFR mutation. However, the potential molecular mechanism that expands the therapeutic benefit of EGFT-TKI in patients who have wild-type EGFR non-small cell lung cancer (wtEGFR NSCLC) remains unclear. Recently, several studies revealed EGFR endocytosis mechanism could mediate signal transductions that influence in cancer cell proliferation. Moreover, our previous study demonstrated that EGFR endocytosis is related to gefitinib sensitivity in wtEGFR NSCLC and EGFR endocytosis could be a novel therapeutic target in lung cancer with wtEGFR (Oncotarget. 2014 15;5(5):1265-78). In this study, we investigated whether EGFR-TKI resistance could be restored in wtEGFR NSCLC cell lines by endocytosis inhibitor phenylarsine oxide (PAO). To investigate effects of PAO in vitro, we analyzed EGF-induced EGFR internalization and performed Annexin V and propodium iodide (PI) staining by flow cytometry. As a result, EGF-induced EGFR endocytosis is decreased and apoptotic cell death is induced accompanied by G0/G1 arrest after PAO treatment. In addition, we observed that cell viability is reduced significantly when PAO and EGFR-TKIs (gefitinib, erlotinib) treated together. Furthermore, we verified signaling transduction that associated with proliferation and apoptosis by western blot. To confirm combination effects of PAO and EGFR-TKI in vivo, we established xenograft mouse model using gefitinib-insensitive SNU1327 cell lines. After Tumor sizes reached 100-200mm3, mice were treated with PAO or gefitinib alone, or combined treatment for 3 weeks. We observed that tumor sizes of combination group were more decreased than other groups.In these result, we validate endocytosis inhibitor PAO is potential drug for overcoming therapeutic limitation of EGFR-TKI in gefitinib-insensitive wtEGFR NSCLC cell lines, though further experiment is needed to explain more accurate mechanism. This study was supported by a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A2057538).
Citation Format: Boyeon Kim, Jae Sook Sung, Yeul Hong Kim. Restoration of EGFR-TKI resistance by endocytosis inhibitor PAO in lung cancer with wild-type EGFR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4680.
Abstract 4684: Modulating the function of multidrug resistance ABCG2 transporter by tyrosine kinases receptor inhibitor cabozantinib
Authors: Zhang Guannan , Zhang Yun-Kai , Wang Yi-Jun , Chen Zhe-Sheng 
Published: July 2016

Abstract
Cabozantinib (XL184) is an oral tyrosine kinases receptor inhibitor which inhibits MET and vascular endothelial growth factor receptor 2 (VEGFR2). Cabozantinib has been approved by Food and Drug Administration for treating advanced medullary thyroid cancer and it is also tested in clinical trials on other solid tumors, including prostate, bladder, ovarian and breast cancer. In the present study, we evaluated the ability of cabozantinib in modulating the function of ABCG2 transporter in drug-selected H460/MX20 cell line and ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2 and ABCG2-482-T7. Cabozantinib at non-toxic level can sensitize the ABCG2-overexpressing cells to antineoplastic drugs mitoxantrone, SN-38 and topotecan. Our results indicated that cabozantinib reversed ABCG2 mediated multi-drug resistance by antagonizing the drug efflux function of ABCG2. However, this reversal effect was not attributed to reduced expression of ABCG2 protein, because ABCG2 protein level was unchanged after treatment of 4μM cabozantinib for 72 hours. Immunofluorescence result showed that cabozantinib did not alter the cellular localization of ABCG2 transporter. Docking analysis indicated that cabozantinib binds to the drug-binding site of ABCG2 transporter. Finally, cabozantinib at 4μM did not significantly change the resistance of ABCB1 overexpressing cell line SW620/AD300 to antineoplastic drug paclitaxel. Overall, our finding demonstrated that cabozantinib potentiates the cytotoxic effects of various antineoplastic drugs that are substrates of ABCG2 and that this is due to modulating the function of ABCG2 transporter.
Keyword: Cabozantinib; ABCG2; Multidrug resistance;
Citation Format: Guannan Zhang, Yun-Kai Zhang, Yi-Jun Wang, Zhe-Sheng Chen. Modulating the function of multidrug resistance ABCG2 transporter by tyrosine kinases receptor inhibitor cabozantinib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4684.
Abstract 4685: Metformin enhances trastuzumab efficacy for HER2+ gastric cancer cells
Authors: Kim Jin-Soo , Kim Geum Ock , Kim Mi Young 
Published: July 2016

Abstract
Background: Trastuzumab is an effective monoclonal antibody against advanced gastric cancers (GCs) with HER2 amplification. Recently, HER2 directed therapies, such as pertuzumab or lapatinib are actively investigated in clinical trials, but showed disappointing results in patients with HER2+ GC. Unfortunately, the efficacy of trastuzumab is limited due to primary and acquired resistance to this agent. Metformin is a widely used antidiabetic drug and shows promising anti-tumor effect in several cancers.
Material and Methods: The following GC cells were evaluated: HER2 amplification -positive (HER2+) and trastuzumab-sensitive NCI-N87 and OE19, HER2+ trastuzumab-resistant OE33 and HER2 negative AGS, H1750 and SNU601. We assessed response of these GC cells to trastuzumab alone or in combination with metformin by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay and anchorage independent growth in soft agar. MGI (mean growth inhibition) was calculated by dividing the colony number of the treated group by that of the untreated control group. Western blots were performed to assess biochemical changes, especially those related with HER2 signaling components.
Results: We observed that treatment with trastuzumab in combination with metformin induced a statistically significant decrease in the number of colonies formed in soft agar by N87 and OE19 cells, as compared to the numbers formed by control cells or cells in the single-treatment groups (Kruskal-Wallis test, p = 0.025, respectively). No growth inhibitory effect was detected in OE33 cells with Compared to trastuzumab alone, the combination of metformin resulted in decreased phosphorylation of HER2 and downstream targets, such as AKT or ERK, in trastuzumab-sensitive HER2+ cells.
Conclusion: Collectively, these data support that trastuzumab and metformin are synergistic in trastuzumab-sensitive HER2+ GC cells. Combination effect on soft agar colony forming assaysCell LinesTrastuzumabMetforminCombinationIndexMGIPMGIPExpectedObservedPNCI-N870.8000.0210.8160.0310.6530.607&lt;0.0011.077OE190.6000.0050.5650.0030.3390.152&lt;0.0012.234OE330.9250.6770.8230.1030.7610.9000.4700.846
Citation Format: Jin-Soo Kim, Geum Ock Kim, Mi Young Kim. Metformin enhances trastuzumab efficacy for HER2+ gastric cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4685.