bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A45: A potential therapeutic strategy for treatment of colorectal cancers through regulating Ras stability via inhibition of Wnt/β-catenin pathway
Authors: Cha Pu-Hyeon , Cho Yong-Hee , Jeong Woo-Jeong , Choi Kang-Yell 
Published: May 2015

Abstract
Ras is a well-characterized proto-oncogene, and its various mutations contribute to transformation and tumorigenesis in a wide variety of human cancers. Although the GTP/GDP loading switch is known as a major regulatory mechanism of Ras, other mechanisms affecting Ras activity are poorly understood. Here, we report a mechanism for controlling Ras activity by regulating its degradation and describe this regulatory mechanism in the suppression of cellular transformation and tumors induced by Ras mutations. We found that negative regulators of Wnt/β-catenin signaling contributed to the polyubiquitin-dependent degradation of Ras following phosphorylation by glycogen synthase kinase 3β (GSK3β) and subsequent recruitment of β-TrCP-E3 ligase. We found a positive association between tumorigenesis and Ras stabilization due to the aberrant activation of Wnt/β-catenin signaling. Our results indicate an essential role for phosphorylation and degradation of Ras and suppression of Ras-induced transformation via the Wnt/β-catenin pathway and provide insight into the role of this novel regulatory mechanism for Ras in tumorigenesis of colorectal cancers (CRCs). Because both Ras and Wnt/β-catenin pathways are frequently activated in CRCs, these results suggest that the regulation of Ras stability through inhibition of the Wnt/β-catenin pathway could be an ideal therapeutic approach for treatment of CRC.
Citation Format: Pu-Hyeon Cha, Yong-Hee Cho, Woo-Jeong Jeong, Kang-Yell Choi. A potential therapeutic strategy for treatment of colorectal cancers through regulating Ras stability via inhibition of Wnt/β-catenin pathway. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A45. doi: 10.1158/1557-3125.RASONC14-A45
Abstract A50: Oncogenic K-Ras accelerates cancer stem cell activation via aberrant Wnt/β-catenin signaling
Authors: Moon Byoung-San , Jeong Woo-Jeong , Choi Kang-Yell 
Published: May 2015

Abstract
Oncogenic K-Ras is known to play an important role in tumor growth, but their involvement in the activation of cancer stem cells (CSCs) is not clear. Here, we show the relationship between K-Ras mutation and CSC activation in the tumorigenesis of colorectal cancer (CRC) by systematic in vitro and in vivo studies as well as by clinical evaluations of human specimens. K-Ras mutation is revealed as an important factor for CSC activation through initial APC loss. The critical role of APC mutation in tumorigenesis involving the activation of CSCs by K-Ras mutation was confirmed by genetic studies using APCMin/+ and K-RasG12D(LA2) mice. We therefore propose that CSC activation by both APC and K-Ras mutations was induced via the Wnt/β-catenin signaling pathway, which was initially activated by APC loss and further enhanced through the Ras-ERK pathway.
Citation Format: Byoung-San Moon, Woo-Jeong Jeong, Kang-Yell Choi. Oncogenic K-Ras accelerates cancer stem cell activation via aberrant Wnt/β-catenin signaling. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A50. doi: 10.1158/1557-3125.RASONC14-A50
Abstract A52: KRAS: The Rarefied Ras Oncogene
Authors: Pershing Nicole L. , Lampson Benjamin , Counter Christopher 
Published: May 2015

Abstract
The Ras family of small GTPases is comprised of three isoforms, HRAS, NRAS and KRAS, which are mutated in up to a third of all human cancers to promote tumorigenesis. Despite nearly identical amino acid sequence, we discovered divergent codon usage between isoform mRNA sequences. Specifically, KRAS is enriched in underrepresented (rare) codons relative to mammalian transcripts, whereas HRAS is characterized by common codons and NRAS is composed of an intermediate codon mixture. Rare codons can limit protein expression, and we tested and found that successively changing rare to common codons increased KRAS protein expression. To determine the impact of rare codon bias on KRAS-driven carcinogenesis, we converted rare to common codons in exon 3 of the endogenous Kras gene, then treated heterozygous Krasex3op/wt mice with the carcinogen urethane to induce Kras mutation-positive lung tumors. We now report that the multiplicity of tumors in these Krasex3op/wt mice was significantly reduced, and only weaker oncogenic mutations were detected in the Krasex3op allele compared to the Kraswt allele. Since high oncogenic RAS expression can induce a senescent growth arrest instead of transformation to a tumorigenic state, we hypothesized that converting rare to common codons in Kras to increase protein expression may augment senescence in response to activating mutations. Indeed, ectopic expression of oncogenic Krasex3op induced a stronger growth arrest in cultured cells than the oncogenic version of the native Kras. In summary, we have identified a novel regulatory mechanism hard-wired into the RAS genes that has a direct impact on tumorigenesis.
Citation Format: Nicole L. Pershing, Benjamin Lampson, Christopher Counter. KRAS: The Rarefied Ras Oncogene. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A52. doi: 10.1158/1557-3125.RASONC14-A52
Abstract B03: Synergistic control of GBM growth by MEK and PI3kinase signaling in a RAS-driven preclinical orthotopic model for human glioblastoma multiforme
Authors: Meskini Rajaa El , Iacovelli Anthony , Kulaga Alan , Gumprecht Michelle , Martin Philip , Baran Maureen , Householder Deborah , Dyke Terry van , Ohler Zoe Weaver 
Published: May 2015

Abstract
PI3K, RTK/RAS, and Rb signaling are commonly altered in human GBM. We utilized a genetically engineered mouse (GEM) model for GBM, designated “TRP,” that expresses GFAP-T121 to suppress Rb (T), the KrasG12D mutation (R), and is heterozygous for a PTEN null allele (P), to develop an efficient and tractable orthotopic mouse model for GBM treatment preclinical evaluation. The orthotopic brain tumors presented linear foci of necrosis with peudopalisading by neoplastic cells described in human GBM, and were highly proliferative, invasive, and vascular. Immunohistochemistry analysis of TRP orthotopic tumors identified markers characteristic of human GBM, and tumor progression was readily examined by serial MRI.
Both PI3K and MAPK pathway inhibitors inhibited growth of TRP GEM-derived primary tumor cells, but did not result in significant apoptosis. However, when GBM derived cells were treated with a combination of pathway inhibitors such as BKM120 (a pan-PI3K inhibitor currently in clinical trials for solid tumors) and PD0325901 (a MEK inhibitor), potency was enhanced with a substantial increase in cell death. Analysis of downstream targets revealed a synergistic effect on target downregulation in the PI3K pathway. In the orthotopic GBM model, the PI3K/MAPK targeted combination delayed tumor growth by increasing GBM cell apoptosis and resulted in significantly increased survival. Taken together, our results validate this new orthotopic model for the assessment of targeted therapeutic regimens for human GBM, and show that the feedback loops and incomplete pathway suppression, observed in vivo with targeted single agents, can be overcome with a combination treatment strategy.
Citation Format: Rajaa El Meskini, Anthony Iacovelli, Alan Kulaga, Michelle Gumprecht, Philip Martin, Maureen Baran, Deborah Householder, Terry van Dyke, Zoe Weaver Ohler. Synergistic control of GBM growth by MEK and PI3kinase signaling in a RAS-driven preclinical orthotopic model for human glioblastoma multiforme. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B03. doi: 10.1158/1557-3125.RASONC14-B03
Abstract B15: NRASG12V oncogene mediates self-renewal in a murine model of acute myelogenous leukemia
Authors: Sachs Zohar , LaRue Rebecca S. , Nguyen Hanh T. , Sachs Karen , Hassan Nurul Azyan Mohd , Diaz-Flores Ernesto , Rathe Susan K. , Sarver Aaron L. , Bendall Sean C. , Ha Ngoc A. , Diers Miechaleen D. , Nolan Garry P. , Shannon Kevin M. , Largaespada David A. 
Published: May 2015

Abstract
Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we employed a murine model that harbors Mll-AF9 and a tetracycline repressible, activated NRAS (NRASG12V). We performed gene expression microarray and RNA sequencing of our AML cells in the presence and absence of NRASG12V. By employing computational approaches to explore NRASG12V-responsive genes in our model, we found that NRASG12V enforced the leukemia self-renewal gene expression signature and was required to maintain an MLL-AF9 and Myb-dependent leukemia self-renewal gene expression program. In functional assays, NRASG12V was required for leukemia self-renewal independently of its effects on growth and survival. We used CyTOF (mass cytometry) for a multiplexed analysis of RAS-dependent signaling intermediates, and found that Mac-1Low cells, which harbor leukemia stem cells, were preferentially sensitive to NRASG12V withdrawal. Using RAS-pathway inhibitors, we found NRASG12V maintained leukemia self-renewal through mTor and Mek pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction. Recent work has shown that NRASG12V has bimodal effects in hematopoietic stem cells (Li et al. Nature 2013). To understand the mechanism of these bimodal effects, we have performed single cell RNA sequencing on our AML model. We expect that these analyses will reveal the cell-type specific NRASG12V –mediated mechanisms of leukemia self renewal.
Citation Format: Zohar Sachs, Rebecca S. LaRue, Hanh T. Nguyen, Karen Sachs, Nurul Azyan Mohd Hassan, Ernesto Diaz-Flores, Susan K. Rathe, Aaron L. Sarver, Sean C. Bendall, Ngoc A. Ha, Miechaleen D. Diers, Garry P. Nolan, Kevin M. Shannon, David A. Largaespada. NRASG12V oncogene mediates self-renewal in a murine model of acute myelogenous leukemia. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B15. doi: 10.1158/1557-3125.RASONC14-B15
Abstract B22: Combined MEK and JAK inhibition rescues mutant hematopoietic stem cell function and provides long-term survival in NrasG12D/G12D mice
Authors: Kong Guangyao , Mark Wunderlich , Yang David , Ranheim Erik A. , Young Ken H. , Wang Jinyong , Chang Yuan-I , Du Juan , Liu Yangang , Tey Sin Ruow , Zhang Xinmin , Juckett Mark , Mattison Ryan , Damnernsawad Alisa , Zhang Jingfang , Mulloy James C. , Zhang Jing 
Published: May 2015

Abstract
Overactive Ras signaling is prevalent in human juvenile and chronic myelomonocytic leukemias (JMML/CMML) that are refractory to conventional chemotherapy. Conditional activation of endogenous NrasG12D/G12D in hematopoietic cells of mice leads to an acute myeloproliferative disease (MPN) that recapitulates many features of JMML and myeloproliferative variant of CMML. We found that as JMML/CMML initiating cells, NrasG12D/G12D hematopoietic stem cells (HSCs) show strong ERK1/2 hyperactivation, hyperproliferation, and depletion with concomitant expansion of downstream progenitors. MEK pathway inhibition alone prolongs the presence of mutant HSCs, but fails to restore their proper function. Consequently, ∼60% of NrasG12D/G12D mice treated with MEK inhibitor alone died within 20 weeks and the remaining animals also displayed significant JMML/CMML-like phenotypes. In contrast, simultaneous inhibition of JAK/STAT signaling, a commonly hyperactivated pathway in human and mouse CMML, more potently inhibits human and mouse CMML cell growth in vitro, sustainably rescues mutant HSC function in vivo, and promotes long-term survival without evident disease manifestation in NrasG12D/G12D mice. Our results provide a strong rationale for combined targeting of MEK/ERK and JAK/STAT in treating JMML and CMML patients.
Citation Format: Guangyao Kong, Wunderlich Mark, David Yang, Erik A. Ranheim, Ken H. Young, Jinyong Wang, Yuan-I Chang, Juan Du, Yangang Liu, Sin Ruow Tey, Xinmin Zhang, Mark Juckett, Ryan Mattison, Alisa Damnernsawad, Jingfang Zhang, James C. Mulloy, Jing Zhang. Combined MEK and JAK inhibition rescues mutant hematopoietic stem cell function and provides long-term survival in NrasG12D/G12D mice. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B22. doi: 10.1158/1557-3125.RASONC14-B22
Abstract B27: SERPINE1 expression is required for HDACi-induced proliferative arrest in ras-transformed epithelial cells
Authors: Higgins Paul J. 
Published: May 2015

Abstract
Malignant transformation of mammalian cells with ras family oncogenes results in dramatic changes in cellular architecture and growth traits. The generation of flat revertants of v-K-ras-transformed epithelial cells by exposure to the histone deacetylase inhibitor sodium butyrate (NaB) was found to be dependent on transcriptional activation of the SERPINE1 gene (encoding the type-1 inhibitor of urokinase and tissue-type plasminogen activators; PAI-1). NaB-initiated SERPINE1 expression preceded induced cell spreading and G1 arrest. To assess the relevance of SERPINE1 induction to proliferative blockade in this cell system more critically, several complementary approaches were used. The addition of a stable, long half-life, recombinant SERPINE1 mutant to SERPINE1-deficient v-K-ras-/c-Ha-ras-transformants or to SERPINE1 functionally null, NaB-resistant, 4HH cells (engineered by antisense knockdown of SERPINE1 mRNA transcripts) resulted in marked cytostasis in the absence of NaB. Transfection of ras-transformed cells with the Rc/CMVSERPINE1 expression vector or infection with an adenoviral SERPINE1 construct, moreover, significantly elevated constitutive SERPINE1 synthesis (10- to 20-fold) with a concomitant reduction in proliferative rate. These data suggest that high-level SERPINE1 expression suppresses growth of chronic ras-oncogene transformed cells and is likely a major cytostatic effector of NaB exposure. Supported by NIH grant GM057242.
Note: This abstract was not presented at the conference.
Citation Format: Paul J. Higgins. SERPINE1 expression is required for HDACi-induced proliferative arrest in ras-transformed epithelial cells. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B27. doi: 10.1158/1557-3125.RASONC14-B27
Abstract B29: A critical role of the SUMO pathway in KRAS-driven oncogenesis
Authors: Yu Bing , Swatkoski Steve , Holly Alesia , Lee Liam Changwoo , Giroux Valentin , Lee Chih-Shia , Carver Joseph , Creighton Chad , Ann David K. , Figg William Douglas , Gucek Marjan , Luo Ji 
Published: May 2015

Abstract
The SUMOylation pathway modulates the activity of many cellular proteins and plays an important role in cellular stress protection. We identified the SUMO E2 ligase Ubc9 to be critical for KRAS-driven transformation in colorectal cancer cells. Ubc9 knockdown severely impairs clonogenic and anchorage-independent growth of KRAS mutant cells in vitro and attenuates tumor growth in xenograft models. Ubc9 mutant studies indicate that Ubc9 enzymatic activity is required for KRAS-driven transformation, thus Ubc9 inhibitor could be potentially useful in this setting. SILAC mass-spectrometry reveals that the SUMOylation of multiple proteins are elevated in KRAS mutant cells. Over-expression of some of these SUMO target proteins partially rescued transformation growth of KRAS mutant cells upon Ubc9 depletion. Our findings suggest a model where the SUMO pathway is required for relieving the oncogenic stress associated with KRAS transformation to maintain cell viability.
Citation Format: Bing Yu, Steve Swatkoski, Alesia Holly, Liam Changwoo Lee, Valentin Giroux, Chih-Shia Lee, Joseph Carver, Chad Creighton, David K. Ann, William Douglas Figg, Marjan Gucek, Ji Luo. A critical role of the SUMO pathway in KRAS-driven oncogenesis. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B29. doi: 10.1158/1557-3125.RASONC14-B29
Abstract B30: Differential network reprogramming by distinct activating K-Ras mutations
Authors: Hammond Dean E. , Mageean Craig J. , Rusilowicz Emma V. , Clague Michael J. , Prior Ian A. 
Published: May 2015

Abstract
In colon cancer, KRAS is most frequently mutated at codon 12, but a significant fraction of patients have mutations at codon 13. Clinical data suggest different outcomes and responsiveness to treatment between these two groups. To investigate the differential effects upon cell status associated with KRAS mutations we performed a quantitative analysis of the proteome and phospho-proteome of isogenic SW48 colon cancer cell lines. Parental cells were compared with cells in which one allele of the endogenous gene has been edited to harbour specific KRAS mutations (G12V, G12D or G13D). Each mutation generates a distinct signature, although the codon 12 mutants overlap significantly whereas G13D is highly divergent and shows more potent up-regulation of phosphopeptide responses. Codon-specific responses within our dataset will be highlighted. Our work raises fundamental questions about basic Ras biology with implications for the design and interpretation of large-scale comparative studies analysing oncogenic Ras signalling. Furthermore, the application of SILAC based quantitative proteomics within a panel of isogenic cell lines represents a promising pipeline for target and biomarker discovery.
Citation Format: Dean E. Hammond, Craig J. Mageean, Emma V. Rusilowicz, Michael J. Clague, Ian A. Prior. Differential network reprogramming by distinct activating K-Ras mutations. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B30. doi: 10.1158/1557-3125.RASONC14-B30
Abstract B35: Dual inhibitors of FT and GGT-1 as novel therapeutic agents for K-Ras-dependent tumors
Authors: Aslamuzzaman Kazi , Zhang Xiaolei , Luo Yunting , Patel Ronil , Fletcher Steven , Cummings Christopher , Lawrence Harshani , Hamilton Andrew , Sebti Said M. 
Published: May 2015

Abstract
Inhibition of mutant H-Ras farnesylation with farnesyltransferase inhibitors (FTIs) blocks its binding to membranes and its ability to activate oncogenic signaling. In contrast, inhibition of K-Ras farnesylation with FTIs leads to its prenylation by geranylgeranyltransferase I (GGT-1), and therefore, inhibition of K-Ras prenylation and oncogenic function requires blocking both FT and GGT-1. Furthermore, several proteins downstream of K-Ras that mediate its malignant transforming activity also require farnesylation (e.g.Rheb) or gernaylgeranylation (e.g. Ral). In addition, the ability of mutant K-Ras to induce lung cancer in mouse models is severely hampered when both FT and GGT-1 are conditionally deficient. These observations prompted us to design small molecule dual FT and GGT-1 inhibitors. In this presentation, the development of FGTI-2734 as a novel therapeutic for K-Ras dependent cancers will be described. The presentation will focus on the effect of this dual inhibitor as compared to the selective FTI-2148 and GGTI-2418 on K-ras prenylation, oncogenic signaling and malignant transformation in cancer cells that depend on K-Ras.
Citation Format: Kazi Aslamuzzaman, Xiaolei Zhang, Yunting Luo, Ronil Patel, Steven Fletcher, Christopher Cummings, Harshani Lawrence, Andrew Hamilton, Said M. Sebti. Dual inhibitors of FT and GGT-1 as novel therapeutic agents for K-Ras-dependent tumors. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B35. doi: 10.1158/1557-3125.RASONC14-B35
Abstract B41: Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices
Authors: Leshchiner Elizaveta S. , Bellairs Joseph , Bird Gregory H. , Opoku-Nsiah Kwadwo , Godes Marina , Walensky Loren D. 
Published: May 2015

Abstract
Activating mutations in KRAS represent the most frequent oncogenic driving force among the RAS homologs K-, N- and H-RAS, and are associated with poor prognosis and chemoresistance. KRAS mutations are present in approximately 30% of tumors, and at even higher frequencies in cancers of the pancreas, lung, thyroid gland, colon, and liver. In pancreatic ductal adenocarcinomas (PDAC), which carries a 5-year survival rate of less than 5%, activating KRAS mutations are present in over 90% of tumors. Moreover, these mutations have been causally linked to the initiation and progression of PDAC. Despite the mechanistic insights into KRAS-mediated oncogenesis, development of high affinity targeted inhibitors remains a formidable challenge. Here, we report the synthesis and application of hydrocarbon-stapled peptides as prototype therapeutics for blocking wild type and mutant KRAS in vitro and in cancer cells. Stabilized Alpha-Helices of SOS1 (SAH-SOS1) were generated by inserting hydrocarbon staples into SOS1 peptide sequence to recapitulate the alpha-helical structure of the native KRAS-interaction domain. SAH-SOS1 peptides, but not negative control analogs, bound to a variety of KRAS constructs with nanomolar affinity, inhibiting nucleotide exchange. This sequence-specific biochemical activity correlated with impairment of KRAS-driven cancer cell viability and signal transduction. These studies provide proof-of-concept for the utility of SAH-SOS1 peptides in dissecting and targeting the oncogenic KRAS pathway in human cancer.
Citation Format: Elizaveta S. Leshchiner, Joseph Bellairs, Gregory H. Bird, Kwadwo Opoku-Nsiah, Marina Godes, Loren D. Walensky. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B41. doi: 10.1158/1557-3125.RASONC14-B41