tbuckley/cabot-search huggingface dataset:
Abstract 4113: Acquired resistance to cetuximab is mediated by HER3 activation in head and neck squamous cell carcinoma
Authors: Yeon Ju Yang, Min Hee Cho, Yoo Jung Oh, Da Hee Kim, Jung Min Kim, Hyung Kwon Byeon, Myung Jin Ban, Ji Hoon Kim, Jae Wook Kim, Min Hee Ku, Jae Moon Yang, Eun Chang Choi, Yoon Woo Koh, Jeong Yeon Lee
Journal: Cancer Research (2017)

Abstract Cetuximab, an EGFR monocloanal antibody, is commonly known to be an effective treatment agent in head and neck squamous cell carcinoma (HNSCC). However, despite the clinical efficacy of cetuximab, a majority of patients with good initial response still suffer from side effects as the acquired resistance to cetuximab. To understand the mechanisms of acquired resistance to cetuximab, we developed a model by exposing a head and neck cancer cell line Cal27 to increasing concentrations of cetuximab and established cetuximab-resistant clones (CETr) derived from the cetuximab sensitive (CETp). We examined how the acquired resistance in the CETr influenced the signaling pathway compared to the CETp. We investigated the effect of lapatinib, a tyrosine kinase inhibitor inhibiting HER3, with or without cetuximab combination on CETr clones and in a xenograft mouse model. Cetuximab-resistant(CETr) clones showed robust overexpression on the HER family receptors HER3. CETr clones also expressed upregulated EGFR, HER2, and HER3 activation resulting in activation of PI3K/ATK and ERK signaling. We also showed that CETr clones exhibited increased EGFR/HER3 dimerization. Treatment of cetuximab and siHER3 RNA together reduced EGFR activation in CETr clones to re-sensitize cells against cetuximab and robustly decreased cell proliferation. Combined treatment of CETr clones with cetuximab and lapatinib led to potent anti-proliferative effects. Co-treatment with cetuximab and lapatinib blocked EGFR, HER2 and HER3 activities and inhibited downstream signaling pathways. Co-treatment resulted in suppression of cell growth more effectively than each drug alone and induced apoptotic cell death through mitochondrial ROS. Furthermore, Co-treatment with cetuximab and lapatinib also led to suppression of tumor growth in orthotopic xenograft mouse model of oral tongue cancer. Our results suggested the upregulation of HER3 as a mechanism underlying resistance to cetuximab in HNSCC, supporting further clinical treatment strategy for tumors displaying acquired resistance to cetuximab. Citation Format: Yeon Ju Yang, Min Hee Cho, Yoo Jung Oh, Da Hee Kim, Jung Min Kim, Hyung Kwon Byeon, Myung Jin Ban, Ji Hoon Kim, Jae Wook Kim, Min Hee Ku, Jae Moon Yang, Eun Chang Choi, Yoon Woo Koh, Jeong Yeon Lee. Acquired resistance to cetuximab is mediated by HER3 activation 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 4113. doi:10.1158/1538-7445.AM2017-4113
Abstract 4947: Her2 inhibition and dormant cell metabolism
Authors: Douglas B. Fox, James V. Alvarez
Journal: Cancer Research (2017)

Abstract Breast cancer is the most diagnosed cancer in women in the United States, and despite improved prognosis resulting from targeted therapies, tumors commonly re-emerge upon development of therapeutic resistance. In order to overcome this, it is critical to explore the cellular pathways that change in tumors following treatment. While many mechanisms of resistance to targeted therapies have been identified, the metabolic changes that occur following treatment have not been well defined. We believe that these changes may offer a general therapeutic target. Using a doxycycline-inducible Her2 mouse model of breast cancer, we are exploring the molecular and cellular consequences Her2 inhibition. Using in vitro mammosphere cultures derived from these mice, we showed that Her2 loss quickly downregulates ERK and Akt signaling. There is a corresponding decrease in proliferation, and apoptosis is induced in 25-50% of cells. However, a population of cells survives Her2 withdrawal and remains dormant for upwards of one month. We are using these models to study how metabolic pathways are rewired following Her2 inhibition, and we believe that the metabolic pathways adapted upon Her2 inhibition may represent targetable vulnerabilities. Note: This abstract was not presented at the meeting. Citation Format: Douglas B. Fox, James V. Alvarez. Her2 inhibition and dormant cell metabolism [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 4947. doi:10.1158/1538-7445.AM2017-4947
Abstract 466: Role of miR-15b-3p in mitoquinone induced autophagy of breast cancer cells
Authors: Francesca Mascia, Kaytee Pokrzywinski, Ashutosh Rao
Journal: Cancer Research (2017)

Abstract Mitoquinone, a redox-active mitochondrially targeted ubiquinone, activates autophagy more potently in breast cancer cells (MDA-MB-231) than in normal breast cells (MCF-12A). Mitoquinone induces the production of reactive oxygen species (ROS) and a concomitant activation of the Nrf2-dependent antioxidant response. MicroRNA are endogenous small double stranded RNA that bind to the 3’ UTR of several target mRNAs and function through translational repression or mRNA degradation. The goal of this study was to evaluate microRNA as a link between oxidative stress and autophagy signaling. We performed RNA sequencing analysis of the microRNAs modulated by mitoquinone treatment of MDA-MB-231 cells. miRNAs were identified using Illumina RNA sequencing. DEseq analysis revealed 97 miRNAs that were differentially expressed at an α &amp;lt; 0.05. Within this set, 15 miRNAs were down-regulated by stimulation with mitoquinone making them attractive as potential autophagy inhibitors. We characterized the role of a miR-15b-3p by transfecting the cells with miR-mimic and anti-miR before inducing an autophagy response. Western blot analysis showed a reduction in the expression of the autophagy marker LC3, the autophagosome chaperon p62 and the transcription factor Nrf2 in presence of the miR-15b-3p mimic. Conversely, miR-15b-3p mimic pre-treatment increased the expression of the cell cycle inhibitor p27 both at the basal level and after mitoquinone stimulation for 48 hrs. The administration of the anti-miR-15b-3p did not change the expression level of these proteins suggesting that miR-15b-3p may work with other miRs toward regulating autophagy. Combining the action of miR-15b-3p mimic with redox active chemotherapeutic drugs could represent a novel strategy for breast cancer therapy by reducing survival signaling through autophagy. Citation Format: Francesca Mascia, Kaytee Pokrzywinski, Ashutosh Rao. Role of miR-15b-3p in mitoquinone induced autophagy of breast 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 466. doi:10.1158/1538-7445.AM2017-466
Abstract 3197: Splicing factors and the role of Navitoclax in drug-resistant ovarian cancer
Authors: Helen M. Coley, Laura Lattanzio, Ornella Garrone, Marco Merlano, Daniela Vivenza, Cristiana Lo Nigro, Nelofer Syed, Alistair Thompson, Bhavya Rao, Tim Crook
Journal: Cancer Research (2017)

Abstract Alternative RNA splicing allows processing of a pre-mRNA into various mature mRNAs. In this way multiple protein products can be derived from a single gene. In cancer it is known that specific splice variants may facilitate malignant transformation and therapeutic resistance. Our current studies focus on the problem of drug resistance in ovarian cancer and we have approached this in a variety of ways. Following sequencing analysis of a panel of ovarian cancer cell lines we identified the RNA splicing factors TCERG and SRSF2 as being reduced in drug resistant ovarian cancer cell lines, compared with their drug sensitive counterpart. TCERG is important in regulating the splicing of variant forms of the BClx gene: BClxL (long form) and BClxs (short form). There are clear implications for drug resistance whereby low TCERG results in reduced BClx splicing to yield the pro-apoptotic BClxs form. In the SKOV-3 human ovarian cancer cell line panel both paclitaxel resistant SKOV-3TaxR and SKOV-3CR carboplatin resistant cells showed reduced levels of TCERG mRNA using qPCR analysis. In addition, qPCR analysis for BClxl and BClxs levels indicated increased ratio of long:short form with drug resistance: SKOV-3 parent line ratio 1.0; SKOV-3TaxR 1.8; SKOV-3CR 1.65. Western immunoblotting showed relatively decreased levels of Bax protein in drug resistant versus drug sensitive cell line in line with a reduced apoptotic reduced. We then explored the use of Navitoclax (ABT0263), the small-molecule Bcl-2 family protein inhibitor for Bcl-xL, Bcl-2 and Bcl-w in our cell line panel. Navitoclax in combination with paclitaxel for 48h gave rise to significantly increased apoptotic response in drug-resistant versus drug sensitive ovarian cancer cell line counterparts, using the Annexin V assay with PI, indicative of re-sensitisation to paclitaxel. Synergistic effects were also seen for the parental cell line but the effects were more marked for the resistant cell lines. Our future work will also involve the use of clinical biopsies of ovarian cancer cases. Citation Format: Helen M. Coley, Laura Lattanzio, Ornella Garrone, Marco Merlano, Daniela Vivenza, Cristiana Lo Nigro, Nelofer Syed, Alistair Thompson, Bhavya Rao, Tim Crook. Splicing factors and the role of Navitoclax in drug-resistant 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 3197. doi:10.1158/1538-7445.AM2017-3197
Abstract 1781: EGFR amplification-A candidate predictive biomarker of PARP inhibitor Talazoparib sensitivity in gliomas
Authors: Shaofang Wu, Feng Gao, Xiaolong Li, Jie Ding, Siyuan Zheng, Emmanuel Martinez-Ledesma, Ningping Feng, Erik Sulman, Roel Verhaak, John de Groot, Dimpy Koul, W.K.Alfred Yung
Journal: Cancer Research (2017)

Abstract Poly (ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARP is a promising strategy for targeting cancers with defective DNA-damage repair. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. Glioma Stem Cells (GSCs) exhibit higher oxidative base damage, single-strand DNA breaks and genomic instability and is reliant on single-strand break repair/base excision repair to tolerate additional stress. PARP critical for maintaining genomic stability by regulating a variety of DNA damage repair mechanisms is constitutively activated in GSCs. In this study, we show that talazoparib – a unique PARP inhibitor exhibits a strong single agent activity to inhibit proliferation of GSCs in vitro and suppress tumor progression in GSCs xenografts. Talazoparib cytotoxic activity was through inhibiting PARylation and by trapping PARP-DNA complexes resulting in accumulation of DNA damage during replication and ultimately leading to apoptosis. More importantly, we found EFGR amplification, which occurs in about 45% of GBM as a biomarker of response to PARPi. Gene expression and RPPA data showed that GSCs with EGFR amplification were associated with increased ROS, basal expression of DNA repair proteins and more DNA damage following talazoparib treatment, which may partially explain the sensitivity of this group of GSCs to talazoparib. EGFR enzyme activity was important for PARPi sensitivity since kinase dead mutant of EGFR or EGFR knock down cell lines were resistant to PARPi as was also shown by decreased PARP/DNA complex formation. Talazoparib showed strong inhibition of tumor growth in subcutaneous glioma model and 20% increase in median survival in an intracranial model with a 10% blood brain penetration of talazoparib. These data provide mechanistic insights into the anti-cancer activity of PARP inhibitors with mechanistic rationale of PARP inhibition and potential EGFR amplification as biomarker in the development for precision cancer. Citation Format: Shaofang Wu, Feng Gao, Xiaolong Li, Jie Ding, Siyuan Zheng, Emmanuel Martinez-Ledesma, Ningping Feng, Erik Sulman, Roel Verhaak, John de Groot, Dimpy Koul, W.K.Alfred Yung. EGFR amplification-A candidate predictive biomarker of PARP inhibitor Talazoparib sensitivity in gliomas [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 1781. doi:10.1158/1538-7445.AM2017-1781
Abstract 2382: RACK1 regulates PKA activity to drive tumorigenesis in colon cancer
Authors: Sheri L. Hayes, Catríona M. Dowling, John C. Coffey, Patrick A. Kiely
Journal: Cancer Research (2017)

Abstract RACK1 (Receptor for Activated C Kinases) is a scaffolding protein with 7 WD repeats that interacts with the Insulin-like Growth Factor I receptor (IGF-IR), integrins, and other signalling proteins. RACK1 functions as a scaffolding protein and regulator of many key biological processes and it is highly expressed in most tissue. We recently reported that RACK1 is essential for IGF-I-mediated regulation of PP2A activity and AGAP2 activity at focal adhesions. Downstream of IGF-1R signaling in cancer cells, the scaffolding properties of RACK1 are altered providing distinct migratory advantages to the cell and suggesting that RACK1 is an important regulator of IGF-I signalling in cancer progression. It is important to further characterise the role of RACK1 in cancer and to delineate the molecular mechanisms by which it regulates key signalling pathways. We have identified Protein Kinase A (PKA) as RACK1 interacting protein. PKA is a complex, multicomponent enzyme which is a fundamental protein that functions in cell survival, proliferation, and cytoskeletal remodelling among others. Our hypothesis is that RACK1 regulates the PKA axis in cancer cells leading to Akt and MAP Kinase activation downstream of IGF-1R signalling. We have demonstrated that RACK1 is required to mediate PKA activity in colon cancer cells. Although we show that PKA expression is not altered in colon cancer tissue, we believe that PKA activity is altered significantly in the disease state. Using PKA inhibitors, we have shown that PKA regulates IGF-I-mediated MAP Kinase activation in colon cancer cell lines. In conclusion, this research project will help elucidate the role of PKA in colon cancer. Inhibiting or promoting specific protein interactions with RACK1 will provide very novel therapeutic opportunities and anti-cancer drug targets. Citation Format: Sheri L. Hayes, Catríona M. Dowling, John C. Coffey, Patrick A. Kiely. RACK1 regulates PKA activity to drive tumorigenesis in colon 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 2382. doi:10.1158/1538-7445.AM2017-2382
Abstract 1518: Mechanisms of bromodomain and extra-terminal motif inhibitor (BETi) sensitivity in triple-negative breast cancer (TNBC)
Authors: Johanna Schafer, Brian Lehmann, Phillip Liu, Matthew Stubbs, Peggy Scherle, Jennifer Pietenpol
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancers (TNBCs) lack expression of estrogen receptor (ER), progesterone receptor (PR), and amplifications in the human epidermal growth factor receptor 2 (HER2). With currently no FDA-approved targeted therapies for TNBC, patients with TNBC have a higher risk of local and distant recurrence, and an overall increased rate of mortality. Recent studies have demonstrated increased sensitivity of TNBC to the anti-proliferative effects of BETi compared to the other breast cancer subtypes. To determine mechanisms of sensitivity to BET inhibition, we analyzed the effect of two BET inhibitors, INCB054329 and OTX-015, across a panel of TNBC cell line models and identified cell lines that were both sensitive and insensitive to BETi. With the intent of identifying biomarkers of sensitivity, we performed RNA-seq and precision nuclear run-on and sequencing (PRO-seq) on both sensitive and resistant cell line models and data generated identified significant differences in key growth regulatory and apoptotic signaling pathways, including notable differences in Myc-dependent signaling. Our data suggest potential biomarkers of BETi sensitivity that may be of value in further pre-clinical studies. Further, our results provide mechanistic rationale for combinations of BETi with select, targeted therapies in a disease that is in need of new therapeutic intervention. Citation Format: Johanna Schafer, Brian Lehmann, Phillip Liu, Matthew Stubbs, Peggy Scherle, Jennifer Pietenpol. Mechanisms of bromodomain and extra-terminal motif inhibitor (BETi) sensitivity in triple-negative breast cancer (TNBC) [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 1518. doi:10.1158/1538-7445.AM2017-1518
OP0327-PARE Your rheum – giving young people a voice in rheumatology research
Authors: K Cresswell, S Parsons, S Stones, JE McDonagh, W Thomson, L Lunt
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Between 2014 and 2016, the Barbara Ansell National Network for Adolescent Rheumatology (BANNAR) commissioned research to explore young people9s rheumatology research priorities and beliefs about research involvement. The next phase of this work has been to establish a UK-wide research advisory group, Your Rheum, to involve 11–24 year olds with rheumatic and musculoskeletal diseases (RMDs) more effectively in shaping research. <h3>Objectives</h3> To describe our experiences of developing a UK-wide research advisory group, for young people with RMDs, using both face-to-face meetings and online involvement approaches. <h3>Methods</h3> From September 2016, we recruited young people to the group using several approaches: including the previous research study database, through BANNAR members, through UK charities, such as Arthritis Care and via social media. To tailor options for involvement, young people were recruited to contribute to both face-to-face meetings and via online channels. <h3>Results</h3> Eight young people attended Your Rheum9s first meeting in October 2016, where they discussed how they would like the group to work. Thirteen young people have been engaged online via a closed Facebook group, monitored by the Your Rheum facilitator. Key challenges in establishing the group have included developing age-appropriate communication approaches to appeal to the range of ages involved, devising ways of ensuring online members remain engaged with the group, and finding appropriate tasks for the group to be involved with, that are both suitable and aligned with research project timings. This involves working closely with young people, health professionals and researchers. <h3>Conclusions</h3> There is both a need for young people9s involvement in research and a desire from young people themselves to do so. Expansion of the online network and involvement activities will allow young people across the UK to have a valuable input into research, regardless of location. <h3>References</h3> What do young people with rheumatic conditions think about being involved in research? 2017, S.Parsons, W.Thomson, K.Cresswell, B.Starling, J.E.McDonagh (unpublished). <h3>Acknowledgements</h3> This abstract presents independent work funded by Arthritis Research UK BANNAR grant 20164 via the Centre for Adolescent Rheumatology at UCL. Supported by the National Institute for Health Research Biomedical Research Unit. We would like to thank all of the young people who took part in the YOURR study and are currently part of Your Rheum, the clinicians, PPI coordinators and other individuals who facilitated their involvement, members of the Barbara Ansell National Network for Adolescent Rheumatology and Arthritis Care. <h3>Disclosure of Interest</h3> None declared
Abstract 342: WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer
Authors: Vassiliki Saloura, Theodore Vougiouklakis, Makda Zewde, Xiaolan Deng, Kazuma Kiyotani, Jae-Hyun Park, Yo Matsuo, Mark Lingen, Naoshi Dohmae, Takehiro Suzuki, Ryuji Hamamoto, Yusuke Nakamura
Journal: Cancer Research (2017)

Abstract While multiple post-translational modifications have been reported to regulate the function of epidermal growth factor receptor (EGFR), the effect of protein methylation on its function has not been well characterized. In this study, we show that WHSC1L1 mono-methylates lysine 721 in the tyrosine kinase domain of EGFR, and that this methylation leads to enhanced activation of its downstream ERK cascade without EGF stimulation. We also show that EGFR K721 mono-methylation not only affects the function of cytoplasmic EGFR, but also that of nuclear EGFR. WHSC1L1-mediated methylation of EGFR in the nucleus enhanced its interaction with PCNA in squamous cell carcinoma of the head and neck (SCCHN) cells and resulted in enhanced DNA synthesis and cell cycle progression. Overall, our study demonstrates the multifaceted oncogenic function of the protein lysine methyltransferase WHSC1L1 in SCCHN, which is mediated through direct non-histone methylation of the EGFR protein with effects both in its cytoplasmic and nuclear functions. Citation Format: Vassiliki Saloura, Theodore Vougiouklakis, Makda Zewde, Xiaolan Deng, Kazuma Kiyotani, Jae-Hyun Park, Yo Matsuo, Mark Lingen, Naoshi Dohmae, Takehiro Suzuki, Ryuji Hamamoto, Yusuke Nakamura. WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck 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 342. doi:10.1158/1538-7445.AM2017-342