bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA13: Discovery of K-Ras inhibitors for the treatment of cancer
Authors: Fesik Stephen W. 
Published: May 2015

Abstract
Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active receptor tyrosine kinases (RTKs) results in the deregulation of cellular signals governing growth and survival in cancer. The guanine nucleotide exchange factor Son of Sevenless (SOS) catalyzes the rate-limiting step in the activation of Ras by exchanging GDP for GTP. SOS is therefore a key control point for the propagation of RTK and Ras signaling. Here we report the discovery of small molecules that bind to a unique pocket on the Ras:SOS:Ras complex, increase SOScat-catalyzed nucleotide exchange, and perturb Ras signaling pathways in cells. X-ray crystallographic studies of Ras:SOS:Ras complexed with these small molecules reveal that they bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of the x-ray structures of multiple co-complexes. In addition, structure-based mutational analyses indicate that this newly identified pocket is essential for compound activity. As predicted, these molecules increase Ras-GTP levels in cells. However, they unexpectedly inhibit MAPK and PI3K signaling. Our studies suggest a novel way to target K-Ras and offer possible starting points for the discovery of compounds that could be used to treat Ras-driven tumors.
Citation Format: Stephen W. Fesik. Discovery of K-Ras inhibitors for the treatment of cancer. [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 IA13. doi: 10.1158/1557-3125.RASONC14-IA13
Abstract IA14: Exploiting context-dependent fragility in oncogenic Ras signaling networks
Authors: White Michael 
Published: May 2015

Abstract
Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among tumors can confound efforts to identify these targets. To help confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a large panel of molecularly annotated non-small cell lung cancer cell lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. This effort revealed actionable targets within onocogenic Ras signaling networks together with collateral vulnerabilities that arise in consequence of oncogenic KRAS expression. Of note, in no case did we find robust synthetic lethal interactions that were attributable solely to the presence or absence of the KRAS oncogene. Rather, detection of significant chemical/genetic interactions required consideration of somatic alterations that co-occur with KRAS mutations at reasonable frequencies in the population. A conceptual extrapolation is that, at least in the setting of lung cancers, KRAS mutation status does not represent a monolithic mechanistic subtype and intervention strategies should account for KRAS-driven vulnerabilities that are specified by discrete genomic contexts.
Citation Format: Michael White. Exploiting context-dependent fragility in oncogenic Ras signaling networks. [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 IA14. doi: 10.1158/1557-3125.RASONC14-IA14
Abstract IA16: Identifying KRAS synthetic lethal interactions using systems biology and functional genomics
Authors: Chen Ron , Gwinn Dana , Sweet-Cordero Alejandro 
Published: May 2015

Abstract
Our laboratory uses cross-species genomic approaches to understand the oncogenic effects of point mutations in KRAS. Using cross-species analysis of mouse models of lung cancer and human lung cancer, we have identified “KRAS signatures” of gene expression and used them to identify key drivers of gene regulation downstream of Kras. A key goal of our laboratory is to reverse engineer these oncogenic signatures to identify key transcriptional regulators which could be inhibited for anti-oncogenic therapy. Previously we used this approach to show that Wt1 is required to bypass a senescence response in cells expressing oncogenic KRAS (Vicent et al JCI 2010). We have now carried out a “second generation” synthetic lethal screen using a more comprehensive computational approach to identify “master regulators” of KRAS-driven gene expression. A focused shRNA screen in a large panel of human NSCLC lines confirmed the synthetic lethality of Wt1 in Kras-mutant tumor lines. In addition, we have identified several other likely “hits.” One of these, TCEB1, is a gene involved in regulating both elongation and the hypoxia response. We are currently carrying out further experiments to elucidate the function of TCEB1 and determine why it is required in cells expressing oncogenic Kras.
Citation Format: Ron Chen, Dana Gwinn, Alejandro Sweet-Cordero. Identifying KRAS synthetic lethal interactions using systems biology and functional genomics. [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 IA16. doi: 10.1158/1557-3125.RASONC14-IA16
Abstract PR07: Crystal structure of K-Ras G12C bound to an active site inhibitor
Authors: Hunter John , Lim Sang Min , Ficcarro Scott B. , Choi Hwan Geun , Gurbani Deepak , Xie Ting , Marto Jarrod A. , Gray Nathanael S. , Westover Ken 
Published: May 2015

Abstract
Activating K-Ras mutations are common oncogenic events in many cancers but effective direct-acting inhibitors have not been developed. Targeting the nucleotide binding site of GTPases like K-Ras has long been dismissed as a possibility because of the high affinity of these proteins for their natural ligands GTP and GDP. We previously reported the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggested that modification of K-Ras with SML-8-73-1 renders the protein in an inactive state. Here we report a crystal structure of K-Ras G12C labeled with SML-8-73-1. The structure reveals that when bound to SML-8-73-1, K-Ras presents in an inactive conformation. This first-in-class covalent K-Ras inhibitor suggests that irreversible targeting of the K-Ras guanine-nucleotide binding site is a viable therapeutic strategy for inhibition of Ras signaling.
This abstract is also presented as Poster B54.
Citation Format: John Hunter, Sang Min Lim, Scott B. Ficcarro, Hwan Geun Choi, Deepak Gurbani, Ting Xie, Jarrod A. Marto, Nathanael S. Gray, Ken Westover. Crystal structure of K-Ras G12C bound to an active site inhibitor. [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 PR07. doi: 10.1158/1557-3125.RASONC14-PR07
Abstract A01: A-803467, a sodium channel blocker, reverses ABCG2-mediated MDR in vitro as well as in vivo
Authors: Anreddy Nagaraju , Kumar Priyank , Patel Atish , Zhang Yun-Kai , Wang Yijun , Kathawala Rishil , Wurpel John D. , Chen Zhe-Sheng 
Published: May 2015

Abstract
The ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2) is a vital member of the ABC transporter superfamily, which has been involved in multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many antineoplastic agents such as doxorubicin and mitoxantrone. ABCG2 expression has been significantly increased in some solid tumors and hematologic malignancies, which is correlated to poorer clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membranous transporter imparts resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the ability of sodium channel blocker, A-803467 to reverse ABCG2-mediated MDR. We found that A-803467 at non-toxic concentration could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies indicated that A-803467 (7.5 μM) significantly increased the intracellular accumulation resulted from inhibition of the efflux of mitoxantrone by inhibiting the transport activity without altering expression level of ABCG2 protein. Furthermore, ATPase analysis indicates that A-803467 stimulates the ATPase activity in membranes overexpressing ABCG2. in-vivo results indicating that tumor volume was significantly decreased by combination of A-803467 with topotecan when compared to the topotecan and A-803467 alone group. Our findings suggest that A-803467 has the potential to be used in combination with ABCG2 chemotherapeutic substrates to augment the response in drug resistant cancers.
Citation Format: Nagaraju Anreddy, Priyank Kumar, Atish Patel, Yun-Kai Zhang, Yijun Wang, Rishil Kathawala, John D. Wurpel, Zhe-Sheng Chen. A-803467, a sodium channel blocker, reverses ABCG2-mediated MDR in vitro as well as in vivo. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A01.
Abstract A04: Changes in matrix metalloproteinase expression in SN-38 resistant colorectal cancer cells
Authors: Berg Spencer I T , Cutler Murray J. , Blay Jonathan 
Published: May 2015

Abstract
The matrix metalloproteinases (MMPs) are a complex family of zinc-dependent proteolytic enzymes, which collectively are capable of degrading all components of the extracellular matrix (ECM). The ECM provides structure and support for normal tissues, and acts both as a barrier to and support for cancer cell invasion and metastasis. MMPs are therefore believed to play an important role in regulating the rate of cancer progression. However, the repeated failure of MMP inhibitors in clinical trials, as well as recent discoveries of novel MMP activities and localizations, has led to a re-evaluation of the roles of MMPs to the cancer process.
In colorectal cancer (CRC) the outlook following disease relapse after surgery and initial chemotherapy is poor, due both to drug resistance and further dissemination of disease. We investigated the involvement of MMPs and related molecules in this context.
We have generated a series of derivatives of the human CRC cell line HT29 that are resistant to SN-38, the active metabolite of the chemotherapeutic agent irinotecan. The principal representative cell line, HT29-S, has a slower proliferation rate than parental HT29 cells, and yet forms denser outgrowths in monolayer culture. The abundance and localization of several MMPs and tissue inhibitors of metalloproteinases (TIMPs) have been assessed in both HT29 and HT29-S cells by western blotting of cytosolic and nuclear protein fractions,and by immunofluorescence. HT29-S cells showed a lower expression of MMP1, MMP7, and MMP9, but also TIMP1 and TIMP2, compared to their parental counterparts, with some differences in cellular distribution. In particular, MMP1 gave a strong nuclear signal by both methods in HT29 cells, which was strongly reduced in HT29-S.
A reduction in MMP expression will allow for an increased accumulation of ECM components. This may act through integrin receptors to activate survival pathways and contribute to the chemoresistance observed in HT29-S cells, and may also facilitate the spread of cancer cells by refining the ECM framework in advanced CRC.
Citation Format: Spencer I T Berg, Murray J. Cutler, Jr., Jonathan Blay. Changes in matrix metalloproteinase expression in SN-38 resistant colorectal cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A04.
Abstract A21: Combined treatment increases the efficacy of chemotherapeutics by downregulating of P-glycoprotein
Authors: Samadi Nasser , Mohseni Mahsa , Ganbari Parisa , tabasinezhad Maryam , Yousefi Bahman 
Published: May 2015

Abstract
Introduction: Understanding the mechanisms of chemoresistance is an urgent need for cancer patients. Induction of drug efflux due to overexpression of P-glycoproteins is considered as an important leading cause of multidrug resistance. In this study, we investigated the role of combination treatments of docetaxel and vinblastine in inhibition of proliferation and induction of apoptosis in H1299 cancer cells. Furthermore, the impact of P-glycoprotein activity in changing the effectiveness of the agents was studied.
Methods: Cell proliferation and the percentage of apoptotic cells were assessed using MTT assay and DAPI staining, respectively. The expression of P-glycoprotein was evaluated in gene and protein levels by Real-time RT-PCR and Western blot analysis, respectively.
Results: Combination treatment of the cells decreased the IC50 concentrations for both docetaxel and vinblastine from 30 nM to 15 nM and 30 nM to 5 nM, respectively (p&lt;0.05). P-glycoprotein mRNA level showed a significant up-regulation in the cells incubated with docetaxel or vinblastine (p&lt;0.001). Combination treatment of the cells neutralized P-glycoprotein overexpression noticeably (p&lt;0.05). Adding P-glycoprotein inhibitor to the cells treated with combined docetaxel and vinblastine, enhanced the efficiency of chemotherapeutics considerably.
Conclusion: Combination therapy along with down-regulation of P-glycoproteins can be considered an important strategy to improve the efficacy of therapeutics.
Note: This abstract was not presented at the conference.
Citation Format: Nasser Samadi, Mahsa Mohseni, Parisa Ganbari, Maryam tabasinezhad, Bahman Yousefi. Combined treatment increases the efficacy of chemotherapeutics by downregulating of P-glycoprotein. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A21.
Abstract A26: Analysis of ABCB1, ABCC1 and ABCG2 expression and clinical parameters in 40 primary retinoblastoma cases
Authors: Castro Blanca Elena , Aguilar Eunice , Cabrera Lourdes , Camacho Javier , Hernandez Adriana , Ramón Guillermo , Sadowinski Stanislaw , Orjuela Manuela , Ponce Veronica 
Published: May 2015

Abstract
Multidrug resistance (MDR) is one of the most important mechanisms involved in chemotherapy failure in cancer. ABC transporters constitute a superfamily of pumps that efflux metabolites, xenobiotics and drugs outside the cell. In many types of malignant tumors some of these transporters are overexpressed causing MDR and consequently tumor progression. ABCB1, ABCC1 and ABCG2 are the ABC transporters whose overexpressions are most frequently involved in chemotherapy failure. Eventhough expression of these transporters has been well studied in many types of adult tumors, expression of ABC transporters and correlation with clinical features have been scarcely reported in retinoblastoma, and intraocular malignant tumor occurring in early infancy. Therefore our objective in this work was to determine ABCB1, ABCC1 and ABCG2 expression by qPCR in untreated primary retinoblastoma cases and to explore whether or not correlations with relevant clinical features do exist. Our results on RNA from 40 retinoblastoma cases naive to chemotherapy treatment, show high mRNA expression of ABCC1 followed by ABCB1 and marginal expression of ABCG2, these results are consistent with immunohistochemistry results from others. ABCC1 was found significantly more expressed in bilateral than unilateral cases.
Citation Format: Blanca Elena Castro, Eunice Aguilar, Lourdes Cabrera, Javier Camacho, Adriana Hernandez, Guillermo Ramón, Stanislaw Sadowinski, Manuela Orjuela, Veronica Ponce. Analysis of ABCB1, ABCC1 and ABCG2 expression and clinical parameters in 40 primary retinoblastoma cases. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A26.
Abstract A27: Transposon mutagenesis screen identifies genes conferring resistance to BRAF inhibition in melanoma
Authors: Chen Li , Dastur Anahita , Yin Xunqin , Benes Cyril 
Published: May 2015

Abstract
Drug resistance states can be affected by altered gene expression levels or functions. We sought to systematically identify genes that could confer resistance to BRAF inhibition in BRAF mutant melanoma by applying a novel transposon mutagenesis screening approach. Resistant genes identified in this study include both well-characterized molecules such as BRAF, CRAF, PTEN and many other genes whose functions have not been previously associated with drug resistance, and encompass functional groups such as signaling pathway components, transcription factors, ubiquitination and sumoylation enzymes, and G-protein coupled receptors. Overexpression of these genes also confers resistance to the MEK inhibitor AZD6244 demonstrating a pathway specific activity. The resistance mechanisms are diverse: some demonstrate elevated ERK or PI3K signaling, while others do not appear to be signaling-related. Two genes identified in this study elicit both ERK and AKT signals and respectively increase the EGFR baseline expression and PLX4720-induced phosphorylation. Combined treatment with EGFR and BRAF inhibitors in these two clones demonstrated marked drug synergy. Taken together with recently published studies implicating EGFR in resistance to BRAF our study indicates that multiple mechanisms of resistance to BRAF inhibitors can converge on EGFR signaling. Our study identifies additional genes that could be used to select patients most likely to benefit from treatments combining EGFR inhibitors with BRAF/MEK inhibitors to overcome resistance.
Citation Format: Li Chen, Anahita Dastur, Xunqin Yin, Cyril Benes. Transposon mutagenesis screen identifies genes conferring resistance to BRAF inhibition in melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A27.
Abstract A46: INCB018424 induces apoptotic cell death through the suppression of pJAK1 in human colon cancer cells
Authors: Eunkyoung Choi , Hana Jung , Hojung Ahn , Seung-Woo Hong , Jai-Hee Moon , Jae-Sik Shin , Kyu-Pyo Kim , Sang Hong Yong , Jae-Lyun Lee , Kyung Choi Eun , Shin Lee Jung , Dong-Hoon Jin , Won Kim Tae 
Published: May 2015

Abstract
Janus kinase (JAK) is one of the main upstream activators of signal transducers and activators of transcription (STAT) that are constitutively activated in various malignancies and are associated with cell growth, survival, and carcinogenesis. Here, we investigated to role of JAKs in colorectal cancer in order to develop effective therapeutic targets for INCB018424, which is the first JAK1/2 inhibitor to be approved by FDA. After examining the basal expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of INCB018424 on the phosphorylation of JAK1/2 using western blot analysis. Cell viability was determined using the trypan blue exclusion assay. The cell death mechanism was identified by the activation of caspase 3 using western blot and annexin V staining. The basal levels of phospho-JAK1 and phospho-JAK2 were cancer cell type dependent. Colorectal cancer cell lines that phosphorylate both JAK1 and JAK2 include DLD-1 and RKO. INCB018424 inactivates both JAK1 and JAK2 in DLD-1 cells but inactivates only JAK1 in RKO cells. Cell death was proportional to the inactivation of JAK1 but not JAK2. INCB018424 causes caspase-dependent cell death, which is prevented by treatment with z-VAD. The inhibition of JAK1 phosphorylation seemed sufficient to allow INCB018424-mediated apoptosis. JAK1 is a key molecule that is involved in colon cancer cell survival and the inhibition of JAK1 by INCB01424 results in caspase-dependent apoptosis in colorectal cancer cells. The use of selective JAK1 inhibitors could be an attractive therapy against colorectal cancer, but further clinical investigations are needed to test this possibility.
Citation Format: Choi Eunkyoung, Jung Hana, Ahn Hojung, Hong Seung-Woo, Moon Jai-Hee, Shin Jae-Sik, Kim Kyu-Pyo, Hong Yong Sang, Lee Jae-Lyun, Choi Eun Kyung, Lee Jung Shin, Jin Dong-Hoon, Kim Tae Won. INCB018424 induces apoptotic cell death through the suppression of pJAK1 in human colon cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A46.
Abstract B19: Functional translation of total RNA packaged in microparticles shed from multidrug resistant cancer cells
Authors: Lu Jamie Fung , Pokharel Deep , Luk Frederick , Bebawy Mary 
Published: May 2015

Abstract
Microparticles (MPs) are submicron (0.1 -1 µM) membrane vesicles released from various cell types including malignant cells. Long considered to be inert cellular debris, MPs have recently been identified to play a crucial role in cellular cross-talk. MPs represent a heterogeneous mixture of surface antigens, proteins, lipids and cytoplasmic components resembling its parental cell. Our previous studies have identified the packaging and transfer of the transcripts, regulatory nucleic acids and proteins which are associated with the acquirement of multidrug resistance (MDR) between cancer cells. In this study we verify the functionality of packaged transcripts via in vitro translation of extracted total RNA from MPs isolated from cancer cells. We confirm the translation of exogenous RNA in a rabbit reticulocyte translation system via Western Blot analysis, 2-D SDS and mass spectrometry. These findings have significance in understanding the impact of MPs on cancer cell biology and reiterate their potential as a target in clinical oncology.
Citation Format: Jamie Fung Lu, Deep Pokharel, Frederick Luk, Mary Bebawy. Functional translation of total RNA packaged in microparticles shed from multidrug resistant cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B19.