bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1773: Targeting HER2 and Src in HER2-driven ovarian and esophagogastric cancers
Authors: Conlon Neil T. , Kroh Keshia , Crown John , Collins Denis M. 
Published: September 2020

Abstract
Background: Neratinib, an oral, irreversible pan-HER tyrosine kinase inhibitor, has exhibited clinical activity against HER2-mutant and HER2 over-expressing cancers. Our previous pre-clinical studies have shown that combining the multi-kinase inhibitor dasatinib with neratinib is highly synergistic in HER2-positive breast cancer. Therefore, the aim of this study was to examine the potential of combining neratinib and dasatinib in HER2 over-expressing/mutant esophagogastric (EG) and ovarian cancer.
Methods: The prevalence of HER2 mutation and amplification levels in ovarian and EG cancers was determined using the AACR Project GENIE database. The anti-proliferative effects of neratinib and dasatinib were assessed by acid phosphatase assay in a panel of HER2-altered ovarian (Caov3, OVCAR8, IGROV-1) and EG (NCI-N87, OE19) cancers. Synergy was assessed using Combenefit software with the Loewe additivity model, with additivity and synergy &gt; 0 and antagonism &lt; 0. Western blotting was used to examine the basal expression of HER2 and downstream signalling activity and to investigate the signalling effects of drug treatment in HER2-mutant OVCAR8 cells.
Results: HER2 was the most commonly amplified gene in EG cancers (14.1%) and was also amplified in 2.4% of ovarian cancers. HER2 mutations occurred in 6.1% of EG and 1.5% ovarian cancers. All five cell lines tested displayed nanomolar sensitivity to single agent neratinib or dasatinib (Table). The combination of neratinib and dasatinib was synergistic in all cell lines. The greatest synergy was observed with low concentrations of neratinib in EG cell lines. Synergistic interactions occurred across a range of concentrations with both drugs in ovarian cancer cell lines. Antagonism was not observed at any concentration tested. Neratinib plus dasatinib inhibited Src and MAPK activity in OVCAR8 cells.
Neratinib and dasatinib in ovarian and EG cancersCell linesCancertypeNeratinib EC50 value (nM)Dasatinib EC50 value (nM)Combination effectNCI-N87Esophagogastric0.188979SynergismOE19Esophagogastric0.432284SynergismOVCAR8Ovarian16281SynergismIGROV-1Ovarian1706SynergismCaov3Ovarian13730Synergism
Conclusions: These data suggest that the addition of dasatinib may enhance the anti-cancer effect of neratinib in HER2-driven ovarian and EG cancers and warrants further investigation.
Citation Format: Neil T. Conlon, Keshia Kroh, John Crown, Denis M. Collins. Targeting HER2 and Src in HER2-driven ovarian and esophagogastric cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1773.
Abstract 1793: Interaction of MYC and SUMOylation machinery in an aggressive pancreatic cancer subtype
Authors: Hassan Zonera , Biederstädt Alex , Schneeweis Christian , Schick Markus , Jonas Nilsson , Wirth Mathias , Coluccio Andrea , Orben Felix , Steiger Katja , Slawska Jolanta , Langston Steve , Saur Dieter , Rad Roland , Reichert Maximilian , Schneider Guenter , Keller Ulrich 
Published: September 2020

Abstract
Despite recent improvements in treatment regimen such as combination chemotherapies, pancreatic ductal adenocarcinoma still carries a dismal prognosis with an overall survival rate of 9%. The oncogenic transcription factor MYC is amplified in about 12% of all PDAC, which is connected to a worse survival. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. Therefore, the aim of the study was to find and to target MYC-associated dependencies.
Human PDAC gene expression data sets were analyzed. Moreover, analysis of the SUMO pathway in large cohort of PDAC was performed by IHC. Furthermore, a novel, pharmacological SUMO inhibitor was used and characterized by using human and murine 2D-, organoid-, and in vivo-models of PDAC. In addition, this connection was also verified by the genetically modified human and murine models.
Large-scale gene expression datasets of human PDACs analysis revealed a connection of MYC to the SUMOylation machinery in PDAC. Moreover, results were also corroborated by the hyperactivation of SUMO pathway in a large patient cohort which characterized a PDAC subtype with a dismal prognosis. We furthermore corroborated these results by using the novel SUMO inhibitor ML093 by in vitro studies that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. In conclusion, SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Citation Format: Zonera Hassan, Alex Biederstädt, Christian Schneeweis, Markus Schick, Nilsson Jonas, Mathias Wirth, Andrea Coluccio, Felix Orben, Katja Steiger, Jolanta Slawska, Steve Langston, Dieter Saur, Roland Rad, Maximilian Reichert, Guenter Schneider, Ulrich Keller. Interaction of MYC and SUMOylation machinery in an aggressive pancreatic cancer subtype [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1793.
Abstract 181: Pan-cancer clinical genomic profiling in circulating tumor DNA from 7345 Chinese advanced cancer patients
Authors: Li Wenhua , Chen Hui , Zhou Yifan , Sun Danpeng , Zhang Bei , Bai Yuezong , Ding Qingqing 
Published: September 2020

Abstract
Purpose: Circulating tumor DNA (ctDNA) sequencing was implemented widely in advanced cancer patients for guiding matched therapy, which could avoid invasive specimen collection and tumor heterogeneous. However, clinical ctDNA genomic profiling of Chinese advanced pan-cancer patients is still unknown.
Methods: 7624 blood samples were obtained from 7345 Chinese patients with advanced solid tumor, including 3506 lung cancer, 860 liver cancer, 674 colorectum cancer, 343 stomach cancer, 329 biliary tract cancer, 324 breast cancer, and 1588 other 17 tumor types. Genomic alterations (GAs), including SNV/Indels, CNVs, and rearrangements were identified via ctDNA sequencing with a 150 cancer-related gene panel. Potentially actionable GAs was annotated according to OncoKB database.
Results: There are 85.2% (6497/7624) samples harbors maximum somatic allele frequency (MSAF) &gt;0.3% and average 5.5 GAs per samples. 21253 known or likely deleterious alterations were identified in 137 genes, and average 3.3 known or likely deleterious GAs per samples. Additionally, 38.4% (2930/7624) samples had at least one potentially actionable GA (PAGA). The most frequently and potentially actionable altered genes were EGFR (13.2%), KRAS (8.6%), PIK3CA (5.1%), ERBB2 (4.0%), FGFR1 (3.6%) and BRAF (3.3%). Importantly, PAGAs in RTK-RAS-MAPK pathway was the most common with 33.7% samples (19.2% SNV/Indels only, 9.8% CNVs only, 1.4% rearrangements only, 3.4% either two or more types of alterations), followed by 5.9% PI3K/AKT/mTOR pathway, 2.1% TP53/cell cycle pathway, 0.8% Epigenetic pathway, 0.1% Hedgehog pathway, and 0.1% DDR pathway. The samples of at least one PAGA in aforementioned pathways were 53.1% in breast cancer, 49.6% in colorectum cancer, 44.0% in bladder/urinary tract cancer, 43.5% in lung cancer, 39.4% in stomach cancer, respectively. In all, 287 cases with PAGAs in RTK-RAS-MAPK pathway (ROS1, ALK, MET) could benefit from crizotinib; 49 cases with PAGAs in RTK-RAS-MAPK pathway (BRAF) could benefit from vemurafenib; 447 cases with PAGAs in PI3K/AKT/mTOR pathway (PIK3CA, PTEN, AKT1, mTOR) could benefit from everolimus; and 6 cases with PAGAs in DDR pathway (ATM) could benefit from olaparib.
Conclusions: The study revealed a comprehensive ctDNA genomic profiling of Chinese patients with advanced solid tumors. And further larger cohorts validation for ctDNA sequencing as a diagnostic tool in target-therapy is needed.
Citation Format: Wenhua Li, Hui Chen, Yifan Zhou, Danpeng Sun, Bei Zhang, Yuezong Bai, Qingqing Ding. Pan-cancer clinical genomic profiling in circulating tumor DNA from 7345 Chinese advanced cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 181.
Abstract 1816: β-catenin antagonist peptide attenuates oncogenic gene transactivation and promotes antitumor activity in breast cancer models
Authors: Rotolo Jim A. , Ghamsari Lila , Gallagher Erin , Ramirez Rick , Koester Mark , Leong Siok , Merutka Gene , Kappel Barry J. 
Published: September 2020

Abstract
Aberrant activation of the canonical Wnt signaling pathway occurs in a variety of cancers, resulting in overactivation of β-catenin-mediated transcriptional activity and increased expression of genes that promote tumor survival, proliferation and inhibit differentiation. Disruption of the β-catenin transcription complex, by inhibiting protein-protein interactions required for its formation, represents a powerful approach to inhibit this previously ‘undruggable' target. The goal of these experiments is to characterize the anti-tumor activity of β-catenin antagonist peptides, BCA1 and BCA2, designed to disrupt the β-catenin transcription complex, in breast cancer models. In in vitro experiments, MCF7 (HER2neg/HRpos) breast adenocarcinoma cells were exposed to β-catenin antagonist peptides, and the impact on β-catenin-mediated gene transactivation was determined by quantitative polymerase chain reaction (qPCR). Results indicate that β-catenin antagonist peptide attenuated oncogenic gene transactivation in MCF7 cells, significantly decreasing the expression of direct β-catenin target genes including Myc, Cyclin D1 and Cyclin-dependent kinase 4 (p&lt;0.05). The impact of β-catenin antagonist peptides on cancer cell viability was quantified by annexin V/PI flow cytometry analysis, indicating a dose-dependent decrease in overall cell viability 48 hours post peptide exposure. Additionally, BCA1 was administered to primary breast cancer tumoroids (HER2pos/HRneg or HER2neg/ HRneg), and the impact on tumoroid viability was quantified by histology and immunofluorescence microscopy. β-catenin antagonist peptide BCA1 resulted in dose-dependent decrease in surviving HER2pos/HRneg and HER2neg/ HRneg breast cancer tumoroids, with EC50 values of 5.2 and 6.9 µM, respectively. Finally, the impact of BCA2, an analogue of BCA1 with an additional N-terminal modification, on subcutaneous MCF7 xenograft tumors was determined in vivo. Administration of 5 mg/kg BCA2 via subcutaneous injection at a dosing frequency of 3x/week for 3 weeks resulted in 18-day tumor regression from the start of treatment and a 63.1% tumor growth inhibition compared to vehicle-treated controls (p&lt;0.05). Taken together, these data demonstrate the significant anti-breast cancer activity of β-catenin antagonist peptides in vitro and in vivo.
Citation Format: Jim A. Rotolo, Lila Ghamsari, Erin Gallagher, Rick Ramirez, Mark Koester, Siok Leong, Gene Merutka, Barry J. Kappel. β-catenin antagonist peptide attenuates oncogenic gene transactivation and promotes antitumor activity in breast cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1816.
Abstract 1824: Coordinate translational control of the kras signaling pathway
Authors: Singh Kamini , Lin Jianan , Lecomte Nicolas , Mohan Prathibha , Leach Steve D. , Ouyang Zhengqing , Wendel Hans-Guido 
Published: September 2020

Abstract
G-quadruplex (GQ) elements are conserved translational control elements that induce a requirement for RNA helicase activity for efficient mRNA translation. Computational structure analyses identify multiple GQ elements in the 5'UTRs of mRNAs encoding KRAS and key downstream signalling molecules. KRAS is a key oncogene in pancreatic ductal adenocarcinoma (PDAC) and many other cancers and except for the specific G12C KRAS mutation we do not have pharmacological inhibitors. We find that KRAS and downstream signalling molecules including PI3K, RALA, RAC2, MYC, MET, and YAP1 strictly depend on the RNA helicase eIF4A for their translation. This implies a potential utility for eIF4A/DDX2 inhibitors. CR31B is a silvestrol analogue that efficiently and selectively blocks eIF4A. CR31B kills PDAC cells at nanomolar concentrations and has significant single agent in vivo efficacy across xenograft, primary PDX, and murine models of PDAC. Together, our findings reveal coordinate, GQ- and eIF4A-mediated control of the translation of key RAS signalling molecules as a vulnerability in KRAS-driven pancreatic cancer.
Citation Format: Kamini Singh, Jianan Lin, Nicolas Lecomte, Prathibha Mohan, Steve D. Leach, Zhengqing Ouyang, Hans-Guido Wendel. Coordinate translational control of the kras signaling pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1824.
Abstract 1877: Hypoxia induces EGFR inhibitor resistance in lung cancer cells by upregulation of fibroblast growth factor receptor 1 (FGFR1) via MAPK pathway
Authors: Lu Yuhong , Liu Yanfeng , Oeck Sebastian , Zhang Gary J. , Glazer Peter M. 
Published: September 2020

Abstract
The development of small molecule tyrosine kinase inhibitors (TKIs) specific for epidermal growth factor receptors (EGFRs) with activating mutations has led to a new paradigm in the treatment of non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis due in part to acquired resistance to conventional therapy. In our previous study, we showed that long-term, moderate hypoxia promotes resistance to the EGFR TKI, gefitinib, in the NSCLC cell line, HCC827, which harbors an activating EGFR mutation. In this study, we found that hypoxia also induces third generation EGFR TKI, osimertinib (AZD9291), resistance in the NSCLC cell line, H1975, which had developed resistance to first and second generation of EGFR TKIs by harboring second EGFR mutation, T790M. Following growth in hypoxia, hypoxia-induced gefitinib resistant HCC827 clones and hypoxic H1975 cells show increased N-cadherin expression and decreased E-cadherin expression, characteristics of an epithelial-mesenchymal transition (EMT), coordinated by an increased expression of ZEB1, an EMT activator. Mechanistically, we show that hypoxia induces increased fibroblast growth factor receptor 1 (FGFR1) expression in HCC827 and H1975 cells, and that knockdown of the FGFR1 by shRNA can attenuate hypoxia induced EGFR TKI resistance in both HCC827 and H1975 cells. We also found the upregulated expression of FGFR1 by hypoxia is mediated through the MAPK pathway to lead to EGFR TKI resistance. In keeping with this, inhibition of FGFR1 function by the selective small molecular inhibitor, BGJ398, attenuates hypoxia-induced EGFR TKI resistance and promotes upregulation of BIM levels. Similarly, inhibition of MEK activity by the inhibitor, trametinib, shows similar effects. In vivo in tumor xenografts in mice, BGJ398 treatment or trametinib treatment suppresses tumor growth and enhances AZD9291 response. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased FGFR1 expression and coordination of EMT in NSCLC. The combination of EGFR TKIs and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLCs.
Citation Format: Yuhong Lu, Yanfeng Liu, Sebastian Oeck, Gary J. Zhang, Peter M. Glazer. Hypoxia induces EGFR inhibitor resistance in lung cancer cells by upregulation of fibroblast growth factor receptor 1 (FGFR1) via MAPK pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1877.
Abstract 1884: The activation of YES1 leads to the acquired resistance to neratinib in HER2-amplified breast and lung cancers
Authors: Yamamoto Hiromasa , Takeda Tatsuaki , Suzawa Ken , Tomida Shuta , Miyauchi Shunsaku , Araki Kota , Nakata Kentaro , Miura Akihiro , Shien Tadahiko , Kitamura Yoshihisa , Sendo Toshiaki , Toyooka Shinichi 
Published: September 2020

Abstract
Background: Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine-kinase inhibitor, and was approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable.
Methods: We established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using various drug exposure conditions. Then we analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance.
Results: YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. Moreover, this combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK.
Conclusion: YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.
Citation Format: Hiromasa Yamamoto, Tatsuaki Takeda, Ken Suzawa, Shuta Tomida, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Akihiro Miura, Tadahiko Shien, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka. The activation of YES1 leads to the acquired resistance to neratinib in HER2-amplified breast and lung cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1884.
Abstract 1894: Role of IGF1R in mediating resistance to MAPK pathway inhibitors in BRAF-mutant melanoma
Authors: Patel Hima , Mishra Rosalin , Broit Natasa , Yacoub Nour , Yuan Long , Alanazi Samar , Hayward Nicholas , Johansson Peter , Garrett Joan T. 
Published: September 2020

Abstract
Melanoma is the most aggressive form of skin cancer originating in the pigment producing melanocytes of the skin. The five year survival rate for patients diagnosed with metastatic melanoma is only 23%. Around 60% of the melanomas encompass the active BRAFV600E oncoprotein, which is critical for survival and proliferation of the melanoma cells as a consequence of hyperactivation of theMAPK pathway. This opened up avenues for development of BRAF inhibitors and subsequently the development of MEK inhibitors. Co-targeting of BRAF and MEK with Dabrafenib and Trametinib respectively, results in a response rate of about 70% in patients harboring the BRAF mutation. The use of these inhibitors is limited as patients relapse on treatment typically within 6 months due to the development of acquired resistance. Recent studies have identified various resistance mechanisms including involvement of various receptor tyrosine kinases. In order to decipher novel mechanisms of resistance, we generated double resistant cell lines to BRAF and MEK inhibitor in WM115, WM983 and A375 human melanoma cell lines harboring BRAFV600 mutations using Dabrafenib and Trametinib over a course of 9-11 months. The drug resistant cell lines exhibited increased viability and maintenance of downstream p-ERK protein as compared to their drug sensitive counterparts. Receptor tyrosine kinase array revealed an increase in phosphorylated HER3, AXL, EGFR and IGF1R in the drug resistant cells versus drug sensitive cells. Quantitative PCR data revealed an upregulation of these molecules along with an increase in the expression of some of their ligands at the mRNA level. RNA-seq analysis identified IGF1R and IGF2BP2 to be upregulatedin the resistant cell lines compared to parental cell lines.IGF2BP2 is a tumor promoter and drives cancer proliferation in a variety of malignancies and is correlated with poor survival.Our next experiments are focused on testing the efficacy of IGF1R inhibitors in the drug resistant cell lines and their downstream effector signaling molecules in vitro and in vivo. Further, we aim to decipher the mechanism by which IGF2BP2 regulates the IGF1R signaling pathway in MAPK inhibitors resistant melanoma setting. Delineating the role of IGF1R in mediating resistance to BRAF and MEK inhibitors will help expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.
Citation Format: Hima Patel, Rosalin Mishra, Natasa Broit, Nour Yacoub, Long Yuan, Samar Alanazi, Nicholas Hayward, Peter Johansson, Joan T. Garrett. Role of IGF1R in mediating resistance to MAPK pathway inhibitors in BRAF-mutant melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1894.
Abstract 1906: Combination MEK and mTORC1/2 inhibition overcomes resistance to single agent therapy in pancreatic cancer
Authors: Brown Wells , Nemirovsky Oksana , Gillespie Jordan , McDonald Paul , Dedhar Shoukat 
Published: September 2020

Abstract
Activating mutations in the KRAS oncogene are found in greater than 90% of pancreatic ductal adenocarcinoma (PDAC), yet KRAS remains difficult to inhibit pharmacologically. Small molecule inhibitors of RAF/MEK/ERK (MAPK) or mTOR are first line treatments for several human malignancies, however resistance to these targeted therapies continues to be a major clinical problem. We show in vitro dose dependent inhibition of proliferation and pERK1/2 in human PDAC cell lines and a KRAS-driven genetically engineered mouse model (GEMM) of pancreatic cancer in response to Trametinib, a small molecule MEK-inhibitor (MEKi). Similarly, Trametinib elicited a dose dependent inhibition of the in vivo tumor growth of a subcutaneous human PDAC xenograft, however these tumors rapidly developed resistance and contained areas of increased activation of pAkt(Ser473). We determined that genetic depletion of KRAS using doxycycline-inducible shRNA or small molecule MEKi leads to increased pAkt(Ser473) and activation of mTORC2 by western blot, implicating activation of the Akt/mTORC1/2 pathway may be a mechanism of resistance to MEKi. Interestingly, treatment of PDAC cell lines with Torin1, a small molecule inhibitor of mTORC1/2, results in the increased activation of pERK1/2, suggesting crosstalk and compensation of these two pathways as mechanisms of resistance. The combination of Trametinib and Torin1 leads to the inhibition of both pERK1/2 and pAkt(Ser473) that is accompanied by a dose dependent, synergistic increase in cytotoxicity not observed with either single agent. In human PDAC xenografts and a syngeneic GEMM, combination treatment of Trametinib and Torin1 dramatically reduced tumor burden and increased survival, without serious toxicity. These results demonstrate that combined inhibition of MEK/ERK and mTORC1/2 is a potent and viable therapeutic strategy for PDAC.
Citation Format: Wells Brown, Oksana Nemirovsky, Jordan Gillespie, Paul McDonald, Shoukat Dedhar. Combination MEK and mTORC1/2 inhibition overcomes resistance to single agent therapy in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1906.