bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2081: NUC 3373 induces endoplasmic reticulum stress in colorectal cancer cells
Authors: McKissock Fiona G. , Prabhakaran Asmithaa , Mullen Peter , Harrison David J. 
Published: August 2019

Abstract
Background
Although 5-fluorouracil-based (5-FU) chemotherapies remain the cornerstone of combination therapies for colorectal cancer (CRC), their clinical utility is limited by key cancer resistance mechanisms associated with breakdown, transport, and activation. This includes the intracellular conversion of 5-FU into its active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), before core anti-cancer activity can be exerted via inhibition of the enzyme thymidylate synthase (TS). NUC-3373, a phosphoramidate transformation of FUDR-MP, is designed to bypass the key resistance mechanisms associated with 5-FU, resulting in a potentially more effective and safer treatment option. In a Phase I dose-finding study, plasma obtained from patients with advanced cancers revealed that NUC-3373 has a longer half-life than 5-FU (9.7 hours vs 8-14 minutes). Herein, we aimed to investigate the potential role of endoplasmic reticulum (ER) stress pathways in the cancer cell response to NUC-3373.
Methods IC50 values for NUC-3373 were established in nine CRC cell lines by sulforhodamine B assay, after which one sensitive (HCT116) and one resistant (SW480) cell line were selected for further characterization. Control experiments were conducted with thapsigargin and tunicamycin. Cells were examined by transmission electron microscopy and, using stereological principles, changes in cell ultrastructure were quantified. Expression of the ER chaperone protein binding immunoglobulin protein (BiP) was detected by Western blot analysis.
Results Ultrastructural analysis revealed that NUC-3373 had differential effects on ER stress that were dependent on cell line sensitivity to the drug. Following treatment, NUC-3373-sensitive HCT116 cells responded by dilation of their ER, while the SW480 resistant cells responded by lengthening of ER but without dilation. These changes were reflected with the two classical ER stress inducers, thapsigargin and tunicamycin. NUC-3373 activated the unfolded protein response (UPR), as evidenced by upregulation of BiP. Both the magnitude and the duration of the BiP response were higher in SW480 cells.
Conclusions This study supports a novel mechanism of action for NUC-3373-induced anti-cancer activity through modulation of cell stress. NUC-3373 induces UPR and ER stress in colorectal cancer cells. Results of the ultrastructural analysis suggest that the sensitivity of cells to NUC-3373 may be determined by the differential adaptation of ER to stress conditions.
Citation Format: Fiona G. McKissock, Asmithaa Prabhakaran, Peter Mullen, David J. Harrison. NUC 3373 induces endoplasmic reticulum stress in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2081.
Abstract 2088: Comprehensive CRISPR screening unravel the different mechanisms of IMiDs resistance
Authors: Zhou Wenrong , Song Tianyu , Long Min , Liu Jiye , Ji Qunsheng , Cang Yong 
Published: August 2019

Abstract
Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4CRBN ubiquitin ligase to trigger proteasomal degradation of the essential transcription factors IKZF1 and IKZF3 and multiple myeloma (MM) cytotoxicity. To have a comprehensive understanding of mechanism underlying sensitivity of MM cells to IMiDs, we performed genome-wide CRISPR-Cas9 screening in three MM cell lines: MM.1S, NCI-H929 and OPM2, which showed resistance to IMiDs at different extent. In the published screening in MM.1S cell, we found that CSN9 signalosome complex, a deactivator of Cullin-RING ubiquitin ligase, regulates MM sensitivity to IMiDs by modulating CRBN expression via SCFFbxo7 ubiquitin ligase. With the newly outcome from H929 and OPM2 cells, we identified 5 top ranking genes with more than 2 sgRNAs ranking in the top 5% sgRNAs in all the three cell lines. CRBN was the top ranking gene with all CRBN-targeting sgRNAs ranking in the top 1% enriched sgRNAs. UbE2G1, reported as an E2 of CRL4-CRBN E3 ligase recently, was another top ranking gene in all the three cell lines. DEPDC5, a component of the GATOR1 complex which inhibits mTORC1 pathway, and SLC35G2, classified as a member of nucleotide sugars transporters (NSTs), were also identified in the top list of all the three cell lines, indicating that mTOR pathway as well as Glycosylation may play an important role in the MM cytotoxicity induced by IMiDs. We also identified 76 top genes shared in two of the three cell lines with more than 2 sgRNAs. Taken together, these results provide a research framework leading to distinguish the cancer patients who become resistant to IMiDs therapy.
Citation Format: Wenrong Zhou, Tianyu Song, Min Long, Jiye Liu, Qunsheng Ji, Yong Cang. Comprehensive CRISPR screening unravel the different mechanisms of IMiDs resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2088.
Abstract 2098: IFIT1 and IFIT3 modulate the drug response in human oral squamous cell carcinoma through interaction and activation of Hsp90
Authors: Pidugu Vijaya Kumar , wu Meei-Maan , Pidugu Hima Bindu , Lee Te-Chang 
Published: August 2019

Abstract
Interferon-induced protein with tetratricopeptide repeats (IFITs) family, well-known interferon-stimulated genes, have multiple tetratricopeptide repeats with helix-turn-helix structural motifs that mediate a variety of protein-protein interactions. Four IFIT genes have been identified in humans: IFIT1, IFIT2, IFIT3, and IFIT5. While the importance of IFIT1 and IFIT3 in the prognosis of cancer has been reported, the molecular basis of IFIT1 and IFIT3 in cancer progression remains unexplored. We have previously shown that high IFIT1 and IFIT3 expression associated with advanced T-stage, lymph node metastasis, perineural invasion, lymphovascular invasion, extranodal extension, and poor overall survival rate in oral squamous cell carcinoma (OSCC) patients. Also, we have demonstrated that high IFIT1 or IFIT3 expression promoted OSCC invasion and metastasis by EGFR signaling via enhancing EGFR endocytic recycling. Intriguingly, our recent studies have revealed the involvement of IFIT1 and IFIT3 in the resistance to chemotherapeutic agents in OSCC cells. The failure of chemotherapy or targeted therapy was often associated with the intrinsic or acquired drug resistance in cancer cells. In the present study, we intended to explore the biological role of IFIT1 and IFIT3 on drug resistance in OSCC cells. Our results showed that ectopic expression of IFIT1 or IFIT3 proteins in OSCC cells significantly increased the resistance to various therapeutic drugs such as cisplatin, carboplatin, 5-FU, and doxorubicin. Whereas, silencing of IFIT1 and IFIT3 by shRNA enhanced the sensitivity to these drugs. We further demonstrated that enhanced expression of IFIT1 and IFIT3 significantly increased the levels of C-terminal phosphorylation of Hsp90 and activation of its client proteins, such as EGFR, AKT, p38, and SAPK/JNK. Using mass spectrophotometric, immunoprecipitation and immunofluorescence analyses, we identified the interactions of IFIT1 and IFIT3 with Hsp90. Suppression of Hsp90 by a specific inhibitor resulted in decreased activation of its downstream targets in IFIT1- or IFIT3-overexpressing cells. These results suggested a novel mechanism of IFIT1 and IFIT3 in activating Hsp90 and several downstream signaling regulators which are crucial for OSCC tumor progression and drug resistance. Thus, IFIT1 and IFIT3 may act as co-chaperones and serve as potentially important prognostic biomarkers for OSCC progression.
Citation Format: Vijaya Kumar Pidugu, Meei-Maan wu, Hima Bindu Pidugu, Te-Chang Lee. IFIT1 and IFIT3 modulate the drug response in human oral squamous cell carcinoma through interaction and activation of Hsp90 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2098.
Abstract 2101: Targeting the root of cancer persister cells using an expressed barcode library
Authors: Oren Yaara , Thakore Pratiksha , Cuoco Mike S. , Cabanos Heidie Frisco , Hata Aaron , Brugge Joan S. , Regev Aviv 
Published: August 2019

Abstract
Despite a favorable initial response, many cancer patients will experience recurrence of disease within months or years after diagnosis. Recurrence largely arises as a result of the growth of residual cancer cells that remain after treatment. The ability of a subset of cells to survive is attributed frequently to genetic heterogeneity, however recently it was shown that in multiple cancer types relapse can arise due to the presence of persister cells. Persisters are a subpopulation of transiently drug-tolerant cells that are able to survive therapy through reversible, non-mutational mechanisms. Tumor dormancy, stochastic cell state shifts and stem cell-like populations are amongst the mechanisms hypothesized to underlie persister phenotype. However, given the lack of high-throughput methods to concurrently track cell state and lineage, it is not currently feasible to distinguish the relative contribution of each of these factors. To address this need, we generated the Watermelon library. The Watermelon library is a high-complexity expressed barcode library that enables simultaneous tracing of lineage as well as the transcriptional and proliferative state of each cell in the population during drug treatment. We have applied the watermelon system to study the mechanisms underlying the ability of a small population of cells to regain proliferative capacity under constant treatment with EGFR tyrosine kinase inhibitors. We combine time-lapse imaging with single-cell RNA sequencing to show that early drug-cyclers do not acquire a facilitating resistance mutation but rather transition to a new cell state. We find that this non-genetic drug-proliferative state is not restricted to a certain clonal lineage and can be reached by distinct transcriptional paths. We anticipate that this unique library, which can be applied to other systems, would facilitate a better understanding of the cellular and molecular pathways that affect non-inherited drug resistance.
Citation Format: Yaara Oren, Pratiksha Thakore, Mike S. Cuoco, Heidie Frisco Cabanos, Aaron Hata, Joan S. Brugge, Aviv Regev. Targeting the root of cancer persister cells using an expressed barcode library [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2101.
Abstract 2112: Structural characterization of transmembrane protein TMEM205
Authors: Bai Xiaoyun , Xia Di 
Published: August 2019

Abstract
Cisplatin resistance is notorious in leading to therapeutic failure of many solid malignancies. Various resistance mechanisms have been proposed while many more are being added, based on the growing number of resistance-inducing genes identified. TMEM205 is an integral membrane protein with unknown function, but its intracellular level was found markedly elevated in cisplatin resistance cells, the mechanism of which is unknown. Here for the first time we characterized the molecular mechanism of TMEM205-mediated cisplatin resistance through structural and functional studies of TMEM205. The crystal structure of the full-length TMEM205 was obtained at 2.5 Å resolution and shows a 4-helix bundle with a highly hydrophilic tunnel. Strong anomalous signals were observed indicating platinum binding sites. Our structural and functional study of TMEM205 provides novel insight into the complexity of cisplatin resistance.
Citation Format: Xiaoyun Bai, Di Xia. Structural characterization of transmembrane protein TMEM205 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2112.
Abstract 2113: KRAS amplification mediates resistance to osimertinib in acquired afatinib-resistant NSCLC harboring exon 19 deletion/T790M in EGFR
Authors: Yamaoka Toshimitsu , Motoi Ohba , Kishino Yasunari , Kusumoto Sojiro , Tsurutani Junji , Ohmori Tohru 
Published: August 2019

Abstract
Background: The second mutation of T790M in epidermal growth factor receptor (EGFR) exon 20 mediates resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs; gefitinib, erlotinib, and afatinib). The critical T790M mutation in EGFR has facilitated the development of third-generation mutation-selective EGFR TKIs (rociletinib and osimertinib). We previously reported heterogeneous afatinib resistance in lung adenocarcinoma PC-9 cells, harboring 15bp deletions in EGFR exon 19. Among the afatinib-resistant PC-9 cells, we noted the emergence of T790M in EGFR exon 20 and responses to third-generation EGFR-TKIs. Here, we used afatinib-resistant lung adenocarcinoma PC-9 cells, called AfaR, harboring the exon 19 deletion/T790M in EGFR.
Purpose: To identify novel resistance mechanisms in post-afatinib treatment, two osimertinib-resistant cell lines, OsiR1 and OsiR2, were established using increasing concentrations of osimertinib by stepwise dose escalation up to 1 μmol/L over 10 to 12 months.
Results: A linear and reversible KRAS amplification and overexpression with increased osimertinib concentrations in OsiR1 and OsiR2 cells, respectively, was detected. OsiR1 cells maintained osimertinib resistance with KRAS amplification after osimertinib withdrawal for 2 months. After osimertinib withdrawal for 2 months, OsiR2 cells exhibited KRAS attenuation and osimertinib sensitivity was entirely recovered in vitro and in vivo. Phospho-EGFR (Y1068) and growth factor receptor-bound protein 2 (GRB2)/son of sevenless homolog 1 (SOS1) complex was found to mediate osimertinib resistance in OsiR1 cells with sustained KRAS activation. The association of phosphorylated EGFR with the GRB2/SOS1 complex leads to KRAS activation. After 2 months of osimertinib withdrawal, the GRB2/SOS1 complex was dissociated, and the EGFR signal but not the GRB2/SOS1 signal was activated. Concomitant inhibition of mitogen-activated protein kinase kinase and EGFR could overcome osimertinib-resistance in OsiR1 cells.
Conclusion: We characterized novel acquired resistance mechanisms for third-generation EGFR-TKI, osimertinib, providing insights into the development of novel treatment strategies.
Citation Format: Toshimitsu Yamaoka, Ohba Motoi, Yasunari Kishino, Sojiro Kusumoto, Junji Tsurutani, Tohru Ohmori. KRAS amplification mediates resistance to osimertinib in acquired afatinib-resistant NSCLC harboring exon 19 deletion/T790M in EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2113.
Abstract 2116: Cariprazine is a potent chemo-adjuvant against multidrug resistant colon and lung cancer
Authors: Hussein Noor , Nyinawbera Angelique , Amawi Haneen , Tiwari Amit 
Published: August 2019

Abstract
Multidrug resistance (MDR) is considered a continuing clinical problem, reducing the efficacy of cancer chemotherapy. The over expression of the ATP - binding cassette (ABC) family G2 (ABCG2) transporter is considered to be one of the main mechanisms responsible for mediating MDR in cancer. Molecular modeling studies have shown the significant affinity and binding mode of cariprazine, a dopamine D3-preferring D2/D3 receptor partial agonist, to the drug binding cavity of ABCG2 with a Glide XP score of the -5.761. Therefore, in this in vitro study, we determined the effect of cariprazine in increasing the efficacy of MX (an ABCG2 substrate) in the ABCG2 overexpressing cancer cell lines H460-MX20 and S1M1-80. Also, studies conducted to determine whether cariprazine is a reversal compound that specifically targets the ABCG2 protein. Alone, cariprazine, at concentrations up to 20 μM, did not significantly decrease cell viability. Cariprazine, at concentrations ranging from 1 to 20 μM, did not significantly alter the cytotoxicity of mitoxantrone (MX) in the parental non-small cell cancer cell line, H460 and colon cancer cell S1. However, cariprazine (1-20 μM) significantly enhanced the efficacy of ABCG2 substrate antineoplastic drug MX in the ABCG2- overexpressing MDR cell line, H460-MX20 and S1M1-80, by reducing the resistance fold from 28 to 1 and from 93 to 1.33, respectively. The intracellular accumulation of rhodamine 123 in the ABCG2-overexpressing cells, S1M1-80 was significantly increased by the addition of cariprazine, in a concentration-dependent manner (1 - 20 μM). Interestingly, 10 or 20 μM of cariprazine significantly decreased the expression levels of the ABCG2 protein in the colon and lung cancer cell lines, suggesting that cariprazine inhibits both the function and
expression of ABCG2 transporters at non-toxic concentrations. Overall, our results suggest that cariprazine, via several distinct mechanisms, can re-sensitize resistant cancer cells to mitoxantrone.
Citation Format: Noor Hussein, Angelique Nyinawbera, Haneen Amawi, Amit Tiwari. Cariprazine is a potent chemo-adjuvant against multidrug resistant colon and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2116.
Abstract 2120: Human epidermal growth factor receptor 3 might be a targetable molecule for treatment of chemotherapy resistant breast cancer
Authors: Kotake Takeshi , Suzuki Eiji , Pu Fengling , Kataoka Tatsuki , Hirata Masahiro , Hohokabe Eri , Toi Masakazu 
Published: August 2019

Abstract
Introduction: Disease control of chemotherapy refractory breast cancer patients (CRBC), who do not respond to conventional treatment strategies, is important. In the setting of neoadjuvant chemotherapy (NAC), susceptibility of the chemotherapeutic agents could be confirmed with clinical relevance. Doxorubicin, docetaxel and paclitaxel have been used as conventional NAC. Eribulin and platinum may also be added in the future. When the drug sensitivity is evaluated by NAC and it is not sensitive to the drugs, there is currently no effective therapy expected to be improved. This is one of the recent unmet medical needs in breast cancer treatment strategy. Materials and Methods: In this study, in order to establish a novel therapeutic strategy for CRBC, we established chemotherapy resistant breast cancer cell lines against doxorubicin, paclitaxel, docetaxel and eribulin using BT549, Hs578t, MDA-MB231, MDA-MB468, and HCC70. We evaluated human epidermal growth factor receptor 3 (HER3) expression in these parental and resistant cell lines. We used U3-1402 (a novel anti-HER3 antibody-drug conjugate) to test if HER3 targeting treatment inhibits the cell proliferation of the chemotherapy resistant cell line with positive conversion of HER3 expression. Results: We found that the change to positive expression of HER3 in paclitaxel resistant BT549 cell line (BT549/PTX) and eribulin resistant Hs578t cell line (Hs578t/ERI) while these two cell lines initially showed negative expression of HER3. In the cell proliferation assay, as we expected, there was no inhibition of proliferation by treatment with HER3 targeting antibody agent U3-1402 in these two cell lines. However, BT549/PTX and Hs578t/ERI with positive conversion of HER3 expression were clearly inhibited their cell proliferation by treatment with U3-1402. Conclusions: It suggests that even in cases whose tumor does not express HER3 initially and show no response for chemotherapy in the NAC, U3-1402 could be effective for the patients with positive conversion of HER3 expression after NAC. We are studying for the role of positive conversion of HER3 expression in the process of acquired chemo-resistance and the elucidation of the molecular mechanism of positive conversion of HER3 expression in these unique treatment condition.
Citation Format: Takeshi Kotake, Eiji Suzuki, Fengling Pu, Tatsuki Kataoka, Masahiro Hirata, Eri Hohokabe, Masakazu Toi. Human epidermal growth factor receptor 3 might be a targetable molecule for treatment of chemotherapy resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2120.
Abstract 2126: Development of a precision chordoma research program
Authors: Groth Marie , Kress Jana , Hajnic Matea , Marinho Joana , Mellert Kevin , Barth Thomas F. , Möller Peter , Dreier Birgit , Plückthun Andreas , Scholl Claudia , Fröhling Stefan 
Published: August 2019

Abstract
Chordomas are malignant tumors of the axial skeleton that originate from remnants of the embryonic notochord. With an incidence of one per million per year, chordoma is a rare disease that accounts for 1-4% of all bone tumors and approximately 20% of primary spinal tumors. As first-line treatment, patients undergo surgical resection followed by adjuvant radiotherapy, whereas most chordomas are resistant to conventional cytotoxic drugs and there are no clinically validated molecular drug targets.
To overcome the lack of effective medical treatment and to better understand chordoma biology, we have established a chordoma precision research program. Here, whole-exome or genome and transcriptome sequencing are used to determine mutational landscapes, DNA copy number profiles, and transcriptome changes in chordoma cell lines and patient samples. Additionally, large-scale functional genomic screens and (phospho-)proteomic analyses have been performed in multiple chordoma cell lines to identify new chordoma-specific vulnerabilities. Based on these multilayered datasets, we selected a panel of previously unrecognized candidate chordoma driver genes, which are currently being validated as novel therapeutic targets using genetic and pharmacologic approaches.
In addition to this unbiased approach, we seek to inhibit the embryonic transcription factor brachyury, an established driver of chordomagenesis. Although brachyury represents, in principle, a promising therapeutic target, inhibition of transcription factors remains difficult. To circumvent this challenge, we are developing Designed Ankyrin Repeat Proteins (DARPins) that specifically prevent the binding of brachyury to DNA. These DARPins are not only a valuable tool for studying chordomagenesis, but also represent a new class of molecularly targeted agents that might be used for the treatment of chordoma patients.
In summary, using multi-omics data, functional genetics, and inhibition of an established chordoma driver, we are working towards a better understanding of chordoma biology and the development of new therapeutic approaches. Updated results of the precision chordoma research program will be presented.
Citation Format: Marie Groth, Jana Kress, Matea Hajnic, Joana Marinho, Kevin Mellert, Thomas F. Barth, Peter Möller, Birgit Dreier, Andreas Plückthun, Claudia Scholl, Stefan Fröhling. Development of a precision chordoma research program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2126.