bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4096: Transglutaminase 2(TG2) induces the intrinsic EGFR-TKI resistance in EGFR-mutant NSCLC
Authors: Choi Junyoung , Yang Hannah , Kim Sang-We , Jung Kyung Hae , Park Kang-Seo , Lee Dae Ho 
Published: July 2017

Abstract
The non-small cell lung cancer (NSCLC) patients with EGFR-sensitive mutations can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib. Unfortunately, even though the intrinsic EGFR-TKI resistant patients harboring the EGFR-sensitizing mutation, a part of those are still resistant to EGFR-TKI. And, it has been reported that both PTEN loss and NF-kB activation contribute to intrinsic EGFR-TKI resistance in EGFR-mutant lung cancer. Transglutaminse 2 (TG2) is post-translational modification enzyme and known to induce degradation of tumor suppressors including PTEN and IκB-α with peptide cross-linking activity. Because TG2 was known as a regulator of PTEN and IκB-α (NF-κB inhibitor) level in cytosol, we have explored if TG2 can be another key regulator to the intrinsic resistance of EGFR-TKI in the intrinsic EGFR-TKI resistant NSCLC cell. In NSCLC with EGFR-sensitive mutations, we first found that higher TG2 expression level and lower PTEN and IκB-α expression levels in the intrinsic EGFR-TKI resistant NSCLC compare with EGFR-TKI sensitive NSCLC. TG2 stably expressing EGFR-TKI sensitive NSCLC cells harboring EGFR mutations showed reduction of both PTEN and IκB-α and exhibited EGFR-TKI resistance. In reverse, TG2 stably downregulated H1650, intrinsic EGFR-TKI resistant NSCLC cell harboring EGFR sensitive mutation, restored EGFR-TKI sensitivity via PTEN and IκB-α restoration by TG2 loss. Xenograft study using TG2 overexpressed and downregulated NSCLC cells also verified our in vitro results. Therefore, we have demonstrated that TG2 elicits the intrinsic EGFR-TKI resistance via PTEN loss and activation of NF-κB pathway. These results suggest that TG2 may be a useful target for overcoming the intrinsic EGFR-TKI resistance of NSCLC harboring EGFR sensitive mutations.
Citation Format: Junyoung Choi, Hannah Yang, Sang-We Kim, Kyung Hae Jung, Kang-Seo Park, Dae Ho Lee. Transglutaminase 2(TG2) induces the intrinsic EGFR-TKI resistance in EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4096. doi:10.1158/1538-7445.AM2017-4096
Abstract 4108: Targeting IL-6 signaling overcomes cetuximab resistance in head and neck squamous cell carcinoma
Authors: O'Keefe Rachel A. , Bhola Neil , Brand Toni M. , Zeng Yan , Johnson Daniel E. , Grandis Jennifer R. 
Published: July 2017

Abstract
Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, has a five-year survival rate of only 50%. The first targeted agent FDA approved for treatment of HNSCC was cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Despite EGFR overexpression in up to 90% of HNSCC tumors and ample evidence supporting EGFR as a therapeutic target in HNSCC, the response rate for single-agent cetuximab is below 20%, and resistance to cetuximab-containing therapy remains a major obstacle in the effective treatment of HNSCC. Identification and targeting of mediators of cetuximab resistance is needed to improve patient outcomes.
Secretion of the cytokine interleukin 6 (IL-6) has been proposed as a mechanism of resistance to cetuximab in HNSCC, and inhibition of signal transducer and activator of transcription 3 (STAT3), a downstream mediator of IL-6 signaling, has been shown to overcome cetuximab resistance in preclinical HNSCC models. Thus, we hypothesize that IL-6 signaling mediates resistance to cetuximab and that co-treatment with agents targeting the IL-6 pathway will enhance the therapeutic efficacy of cetuximab in HNSCC.
We have generated cetuximab-resistant variants of the cetuximab-sensitive HNSCC cell lines Cal33 and PE/CA-PJ49. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis indicated that IL6 expression is increased 3.5- to 8-fold in cetuximab-resistant variants compared to the parental cells from which they were derived. In addition, a colony formation assay revealed that, as expected, cetuximab-treated parental cells formed fewer colonies than vehicle-treated cells, while cetuximab treatment had no effect on the ability of cetuximab-resistant PE/CA-PJ49 variants to form colonies. In contrast, treatment with tocilizumab, an IL-6 receptor-neutralizing monoclonal antibody, markedly reduced the colony-forming ability of the cetuximab-resistant variants, but not parental cells. These results suggest that targeted inhibition of IL-6 signaling may effectively inhibit proliferation in cetuximab-refractory HNSCC cells.
Citation Format: Rachel A. O'Keefe, Neil Bhola, Toni M. Brand, Yan Zeng, Daniel E. Johnson, Jennifer R. Grandis. Targeting IL-6 signaling overcomes cetuximab resistance in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4108. doi:10.1158/1538-7445.AM2017-4108
Abstract 4111: EGFR wild type allele amplification induces acquired resistance to mutation-specific EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells
Authors: Kobayashi Keigo , Nukaga Shigenari , Yasuda Hiroyuki , Masuzawa Keita , Hamamoto Jyunko , Kawada Ichiro , Naoki Katsuhiko , Mimaki Sachiyo , Matsumoto Shingo , Goto Koichi , Tsuchihara Katsuya , Betsuyaku Tomoko , Soejima Kenzo 
Published: July 2017

Abstract
Purpose:
Third-generation EGFR-tyrosine kinase inhibitors (TKIs) are mutation-specific inhibitors that generally have minimal effects on wild type protein. The mechanisms underlying acquired resistance to third-generation EGFR-TKIs remain relatively uncharacterized. The purpose of this study is to clarify the mechanisms of acquired resistance to third-generation EGFR-TKIs in order to improve the prognosis of lung cancer patients harboring EGFR mutations.
Experimental design:
We established third-generation EGFR-TKIs resistant cells using a dose-escalation method. The PC9 (EGFR E746-A750del) and H1975 (EGFR L858R+T790M) human NSCLC cell lines were cultured with rociletinib (CO-1686) or osimertinib (AZD9291) for several months. Their resistance to a third-generation EGFR-TKIs was confirmed by the MTS cell proliferation assay. To clarify the heterogeneity of potential resistance mechanisms, those resistant cell lines were subcloned to isolate resistant clones. DNA isolated from the parental and resistant cell clones was then subjected to whole exome sequencing. Copy number alterations and several genetic alterations potentially relevant to EGFR-TKIs sensitivity were detected.
Results:
We identified Src-AKT pathway contribute to acquired resistance. In addition, we identified that EGFR wild type allele, but not mutation allele, amplification induced acquired resistance. It mirrors the decreased inhibitory pressure for wild type EGFR by mutation-specific EGFR-TKIs.
Conclusion:
We provide evidence of wild type allele-mediated resistance, a novel concept of acquired resistance, occurring in response to mutation-specific inhibitor therapy in cancer treatment.
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Citation Format: Keigo Kobayashi, Shigenari Nukaga, Hiroyuki Yasuda, Keita Masuzawa, Jyunko Hamamoto, Ichiro Kawada, Katsuhiko Naoki, Sachiyo Mimaki, Shingo Matsumoto, Koichi Goto, Katsuya Tsuchihara, Tomoko Betsuyaku, Kenzo Soejima. EGFR wild type allele amplification induces acquired resistance to mutation-specific EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4111. doi:10.1158/1538-7445.AM2017-4111
Abstract 412: Genetic variation in platinum-sensitive and platinum-resistant high-grade serous epithelial ovarian cancer
Authors: Castellano Tara , Clark Leslie H. , Rashid Naim , Bae-Jump Victoria 
Published: July 2017

Abstract
Background: We examined the association of platinum resistance with genetic mutations in high grade serous ovarian cancer (HSOC) patients undergoing high-throughput genomic tumor sequencing.
Methods: Snap-frozen and fresh frozen paraffin embedded tissue samples were collected from HSOC patients enrolled on UNCseq (NCT01457196). UNCSeq is an institutional protocol which uses next generation sequencing to detect genetic mutations in a wide array of malignancies. Illumina libraries were prepared separately from tumor and a matched normal sample from each patient. Relevant targets were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Samples were sequenced on Illumina HiSeq machines in a variety of formats. Mutations with a quality score &lt;100 were filtered from the data set, and only mutations rated to have a moderate to high impact were retained. Medical record review determined platinum sensitivity or platinum resistance. Tumors were defined as platinum sensitive or resistant if patients were noted to have &gt; or &lt; 6 months of disease free interval following completion of induction therapy, respectively.
Results: Overall 39 HSOC cases met inclusion criteria; 32 tumors met criteria for platinum sensitive and 7 platinum resistant. 308 mutations were noted in at least one individual across all patients. The top observed mutations in platinum sensitive HSOC were TP53 (41%, n= 13), GucylA2 (19%, n=6), MLL2 (19%, n=6) and MTOR (16%, n=5). The top observed mutations in platinum resistant tumors were TP53 (71%, n=5), TET1 (43%, n=3), NF1 (43%, n=3) and MLL3 (43%, n=3). There was a trend toward more p53 mutations in resistant tumors (71% versus 41%, p=0.21) There was no difference in the total number of mutations per tumor in platinum sensitive and resistant patients, (3 vs. 4, p=0.516).
Conclusions: We did not detect a difference in the number of genetic mutations in HSOC according to platinum sensitivity. Platinum resistant tumors had a trend toward higher frequency of TP53 mutations than platinum sensitive HSOCs. Furthermore, we identified 3 frequently mutated genes in platinum resistant HSOC: TET1, an epigenetic regulator, NF1, a tumor suppressor gene and MLL3, a histone modifier gene. Ongoing tumor sequencing of HSOCs on UNCseq will help to confirm these results.
Citation Format: Tara Castellano, Leslie H. Clark, Naim Rashid, Victoria Bae-Jump. Genetic variation in platinum-sensitive and platinum-resistant high-grade serous epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 412. doi:10.1158/1538-7445.AM2017-412
Abstract 4121: Androgen receptor as a potential target in non-small cell lung cancer
Authors: Brennan Sean , Wang Albert R. , Beyer Hope , Wiese Dylan , Buehler Darya , Saeed Anwaar , Baschnagel Andrew M. , Iyer Gopal 
Published: July 2017

Abstract
The cancer genome atlas (TCGA) has identified androgen receptor (AR) to be mutated, deleted and amplified across human lung squamous cell carcinoma and adenocarcinoma. Expression of AR is critical for early lung development. However, the intriguing expression of AR in non-small cell lung cancer (NSCLC) opens up an alternative treatment paradigm in the event of onset of clinical resistance to lung cancer drugs. To investigate this potential, a) 10 NSCLC cell lines and 3 control prostate cancer cell lines were stimulated with synthetic AR agonist, R1881 at 24, 48 and 72 hours. 0.5-4-fold RNA and protein expression was found across these lung cancer cell lines when compared to unstimulated cells. b) droplet digital PCR revealed varying copies of AR DNA when benchmarked to prostate AR. c) cell proliferation assays of these cell lines with enzalutamide (MVD3100) treatment resulted in 50-65% cell survival at concentrations ranging from 10 - 25 µM. d) Immunohistochemical staining of AR in a NSCLC human tissue microarray (TMA) revealed 10 out of 88 patients (11%) to have AR positive staining in their tumor. This included 6 adenocarcinomas and 2 squamous cell carcinomas. 8 patients had focal while 2 had diffuse staining. Validation of the TMA performed with whole mount slides confirmed diffuse staining in these 11 samples. Taken together, these findings suggest AR is a potential therapeutic target in NSCLC and further work is underway to test these observations in drug resistant lung cancer cell lines and pre-clinical mouse models.
Citation Format: Sean Brennan, Albert R. Wang, Hope Beyer, Dylan Wiese, Darya Buehler, Anwaar Saeed, Andrew M. Baschnagel, Gopal Iyer. Androgen receptor as a potential target in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4121. doi:10.1158/1538-7445.AM2017-4121
Abstract 4132: Roles of the acetyltransferases CBP/p300 in breast cancer
Authors: Muhmud Iqbal , Tian Guimei , Liao Daiqing 
Published: July 2017

Abstract
Intrinsic drug resistance renders certain breast cancer (BC) patients unresponsive to standard-of-care therapies. For example, ~50% of patients with estrogen receptor-positive (ER+) tumors do not respond to endocrine therapies (ETs, e.g., tamoxifen). Acquired drug resistance is another cause for treatment failure and deadly relapse. Therefore, new strategies that tackle both intrinsic and acquired resistance are needed for improving clinical outcome for BC patients. ER-alpha, the defining factor for ER+ tumors, is an estrogen-activated transcription factor (TF) that drives tumor growth and progression. It critically depends on the coactivators CBP/p300 for gene expression underpinning tumor biology of ER+ subtypes that account for ~75% of all BC cases. Recent advances revealed that another hormone receptor, the androgen receptor (AR), is expressed in the majority of ER+ BCs as well as in a subset of ER- BCs. Evidence has shown that AR signaling is implicated in ET resistance. For the HER2-enriched tumors, high levels of AR expression correlate with poor prognosis. Similarly for ER-alpha, CBP/p300 act as key coactivators for AR-mediated gene expression. Additionally, other oncogenic TFs (e.g., beta-catenin/TCF and STAT3) also depend on CBP/p300 for gene activation. Importantly, these pathways are active in all BC subtypes, regardless of the hormone receptor status. CBP/p300 overexpression and heightened acetyltransferase activity are detected in clinical BC samples and correlate with disease progression. Thus, CBP/p300 represent attractive targets for developing novel therapies broadly applicable for treating all major BC subtypes. We have discovered a novel class of highly potent CBP/p300 inhibitors. Our previous studies indicated that this class of compounds is highly effective to suppress tumor growth in vivo using a xenograft mouse model. We will present genomic features of CBP/p300 in different breast cancer subtypes and experimental data underlying potential mechanisms by which CBP/p300 regulate oncogenic phenotypes, as well as effects of pharmacologic inhibition of CBP/p300 on sensitivity of breast cancer cells to standard anticancer therapeutics.
Citation Format: Iqbal Muhmud, Guimei Tian, Daiqing Liao. Roles of the acetyltransferases CBP/p300 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4132. doi:10.1158/1538-7445.AM2017-4132
Abstract 415: In vivo shRNA library screening to identify novel targets for head and neck squamous cell carcinoma
Authors: Pickering Curtis R. , Xie Tongxin , Kumar Manish , Parimi Ramya L. , Yang Liang P. , Wang Jiping , Seth Sahil , Bristow Christopher A. , Carugo Alessandro , Robinson Frederick S. , Draetta Giulio F. , Skinner Heath , Frederick Mitchell J. , Myers Jeffrey N. 
Published: July 2017

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a diverse group of tumors from the upper aerodigestive tract that are treated primarily with surgery, chemotherapy, and/or radiation. Recent genomic studies have characterized the genomic alterations in HNSCC but they failed to identify novel oncogenic drivers for therapeutic targeting. In order to identify novel targets we have utilized an in vivo shRNA library screening platform in a panel of genomically characterized HNSCC cell lines. The screens were performed alone or in combination with platinum-based chemotherapy or radiation, and the screening libraries included known druggable targets, DNA repair genes, and HNSCC candidate driver genes. Initial results indicate that this in vivo screening is able to identify targets that may not be found through traditional in vitro screening approaches and related to tumor-stromal interactions and metabolism. These genes emphasize the importance of including the tumor microenvironment in studies to understand driver genes and identify novel therapeutic interventions.
Citation Format: Curtis R. Pickering, Tongxin Xie, Manish Kumar, Ramya L. Parimi, Liang P. Yang, Jiping Wang, Sahil Seth, Christopher A. Bristow, Alessandro Carugo, Frederick S. Robinson, Giulio F. Draetta, Heath Skinner, Mitchell J. Frederick, Jeffrey N. Myers. In vivo shRNA library screening to identify novel targets for head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 415. doi:10.1158/1538-7445.AM2017-415
Abstract 4153: CRISPR/Cas9-based oncogene editing enables characterization of rare mutations in cancer cells
Authors: Plenker Dennis , Sos Martin L. 
Published: July 2017

Abstract
In the past decade new insights into key oncogenic pathways and the development of targeted therapies enabled the success of precision medicine. However, only a small part of the cancer genome can be targeted effectively. This is in part due to the fact that the number of cancer cell models for a given oncogenic mutation is limited. We hypothesized that CRISPR/Cas9-mediated genome editing may enhance the ability to functionally study rare genomic lesions or resistance mutations that arise in patients under therapy. As a proof of concept we established, genetically modified PC9 lung cancer cells that harbor an activating EGFR ex19 deletion (EGFRdel E746-A750) into double mutated (EGFRdel E746-A750+T790M) or triple mutated (EGFRdel E746-A750+T790M+C797S) EGFR in order to induce resistance against known EGFR inhibitors. These cell lines fully recapitulated the phenotypic response pattern to first and third generation EGFR inhibitors that have been observed in patients harboring these clinically relevant resistance mutations. In a next step we switched the dependency of PC9 cells from the intrinsic oncogenic EGFR mutation into a rare ex20 SVDins mutation (EGFRD770_N771insSVD) that is typically associated with resistance towards all known EGFR inhibitors. Again, we observed a shift in the response to targeted inhibition of EGFR when compared to parental cells. Since the methodological principles can be applied to an array on known oncogenic mutations our approach may serve as a versatile platform for the functional study of oncogenic mutations that are found in patients. We envision that such reprogrammed cells may be of use for the screening of novel targeted therapeutics and therefore may enable the development of mutation specific drugs that are currently lacking for the majority of patients.
Citation Format: Dennis Plenker, Martin L. Sos. CRISPR/Cas9-based oncogene editing enables characterization of rare mutations in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4153. doi:10.1158/1538-7445.AM2017-4153
Abstract 4164: TRAIL resistance of glioblastoma cells is associated with DNA damage signalling network
Authors: Sur Idot;lknur , Muslu Kerem , Cingöz Ahmet , Önder Tuğba Bağcı 
Published: July 2017

Abstract
To reduce the risk of ageing associated dysfunctions and maintain the genomic stability, cells need a complex DNA repair mechanisms. Defects in this pathway or accumulation of DNA damage lead to genome instability, tumorigenesis, and ageing. Chemotherapy and radiotherapy are designed to kill cancer cells by inducing DNA damage and triggering cellular ageing. Surgery followed by combined chemotherapy and radiotherapy is currently the standard therapy for glioblastoma multiforme (GBM) which is the most common primary brain tumor. TNF related apoptosis-inducing ligand (TRAIL) is promising anti-cancer agent for GBM therapy, as it induces apoptotic death in only cancerous cells, but not in normal cells. However, the mechanisms underlying TRAIL resistance in GBM have remained elusive. To understand the role of DNA damage response (DDR) mechanism and develop more effective therapeutic approaches, TRAIL resistant and sensitive T98G cells were generated. The effect of DDR proteins (H2AX (Ser319), ATM total, ATR total, CHK1 total, CHK2 total, ATM (Ser1981), ATR (Ser428), CHK1 (Ser345), CHK2 (Ser19) and 53BP1) on TRAIL resistance was detected in TRAIL resistant and sensitive T98G cells. These proteins showed different level of protein expressions in TRAIL resistance and sensitive T98G cells. Most remarkable difference was found in the level of phosphorylated kinase CHK2 (Ser19) with higher expression level in TRAIL resistant T98G cells than TRAIL sensitive T98G cells. Therapies that inhibit CHK2 (Ser19) levels in glioma may enhance the efficacy of TRAIL treatment. In immunofluorescence analysis, increased number of γH2AX foci was noted upon TRAIL treatment. These findings demonstrate that DNA damage signalling pathways contribute to TRAIL resistance and targeted inhibition of DNA repair factors can provide the most effective therapeutic strategies to overcome TRAIL resistance of GBMs. Moreover, the information from this study may hold answers for cancer research in future and serve as a potential suppressor for the treatment of cancer.
Citation Format: İlknur Sur, Kerem Muslu, Ahmet Cingöz, Tuğba Bağcı Önder. TRAIL resistance of glioblastoma cells is associated with DNA damage signalling network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4164. doi:10.1158/1538-7445.AM2017-4164