bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4549: CDK2 inhibition causes anaphase catastrophe through the centrosomal protein CP110
Authors: Hu Shanhu , Danilov Alexey V. , Godek Kristina M. , Orr Bernardo , Tafe Laura J. , Memoli Vincent A. , Galimberti Fabrizio , Ravi Saranya , DeCastro Andrew J. , Lu Yun , Mustachio Lisa Maria , Sekula David J. , Andrew Angeline S. , Freemantle Sarah J. , Compton Duane A. , Dmitrovsky Ethan 
Published: May 2015

Abstract
Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Whether aneuploidy is an anti-neoplastic target remains to be learnt. We previously uncovered an unrecognized consequence of Cdk2 inhibition that causes lung cancer cells to undergo anaphase catastrophe, growth inhibition and apoptosis. Cells with activating KRAS mutations were especially sensitive to Cdk2 inhibition. The mechanism of Cdk2-mediated anaphase catastrophe and how activated KRAS promotes this effect was the subject of this study. Live-cell imaging provided direct evidence that after Cdk2 inhibition, lung cancer cells develop multipolar anaphase, undergo multipolar cell division, and the fate of the progeny of these divisions is apoptosis and death. The centrosomal protein CP110, a Cdk2 target protein, was found to be a critical mediator of Cdk2-inhibition-driven anaphase catastrophe. Intriguingly, siRNA-mediated CP110 repression induced anaphase catastrophe of lung cancer cells. By contrast, overexpression of CP110 antagonized anaphase catastrophe caused by Cdk2 inhibition. Furthermore, we found that activated KRAS mutations sensitized lung cancer cells to Cdk2 inhibition by deregulating CP110 expression. Immunohistochemical examination of a paired normal-malignant lung cancer tissue array revealed a statistically significant upregulation of CP110 in lung cancers as compared with normal lung tissues. Notably, CP110 expression was reduced in smokers where KRAS mutations are frequently present. Taken together, this study presents a CP110-dependent pathway that engages anaphase catastrophe in lung cancer cells. It also provides a mechanistic explanation that lung cancers and potentially other cancers with activated KRAS mutation are more sensitive to Cdk2 inhibition due to CP110 deregulation.
Citation Format: Shanhu Hu, Alexey V. Danilov, Kristina M. Godek, Bernardo Orr, Laura J. Tafe, Vincent A. Memoli, Fabrizio Galimberti, Saranya Ravi, Andrew J. DeCastro, Yun Lu, Lisa Maria Mustachio, David J. Sekula, Angeline S. Andrew, Sarah J. Freemantle, Duane A. Compton, Ethan Dmitrovsky. CDK2 inhibition causes anaphase catastrophe through the centrosomal protein CP110. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4549. doi:10.1158/1538-7445.AM2014-4549
Abstract 4619: Protein palmitoylation in non-small cell lung cancer (NSCLC): DHHC5 palmitoyltransferase as a potential therapeutic target
Authors: Tian Hui , Lu Jui-Yun , Shao Chunli , Huffman Kenneth , Carstens Ryan , Minna John D. , Hofmann Sandra L. 
Published: May 2015

Abstract
Post-translational palmitoylation of intracellular proteins is mediated by protein palmitoyltransferases (PAT) belonging to the DHHC family, which share a common catalytic Asp-His-His-Cys (DHHC) motif. According to a genome-wide siRNA screen scoring for growth suppression in over 50 non-small cell lung cancer (NSCLC) cell lines, DHHC family members are strikingly over-represented. Among the tested DHHC palmitoyltransferases, knockdown of DHHC5 showed cell growth inhibition in many cell lines in the initial screen.
To further investigate the growth suppression in response to DHHC5 depletion, transient and stable knockdowns of DHHC5 were undertaken in a dozen of NSCLC cell lines identified in the genome-wide screen using siRNAs and lentiviral shRNAs. Such knockdown was also performed in three immortalized human lung bronchial epithelial cell lines (HBECs). The gene expression and protein levels of DHHC5 were analyzed by RT-PCR and immunoblotting, both of which showed efficient knockdown levels. Cell proliferation and anchorage-dependent/independent colony formation assays indicated that DHHC5 knockdown led to cell growth arrest and decreased cell clonogenicity in most of the tested NSCLC cell lines in vitro, but not in the HBECs. H1299, H358 and H2009 cell lines were particularly dependent on DHHC5 expression and the growth-suppression phenotype of DHHC5 stable knockdown H1299/H358/H2009 cells was rescued by overexpression of DHHC5. The catalytically inactive DHHC5 mutant was not able to provide rescue. In vivo tumor formation assays were then carried out by injecting H1299 and H358 control cells and DHHC5 stable knockdown cells subcutaneously into NOD/SCID mice. DHHC5 knockdown led to absence or dramatically decreased tumor xenograft formation. Furthermore, a Tet-On inducible system with TRIPZ shRNA lentiviral delivery was established in H1299. Mouse xenografts using this H1299 Tet-on inducible cell line showed similar results.
As DHHC5 function is needed for optimal lung cancer cell growth, it will be important to identify physiologically relevant substrates in order to develop inhibitors of DHHC5 function. Future plans include microarray and protein kinase array analysis to distinguish possible signaling pathways in which DHHC5 may be involved, as well as palmitoyl-protein profiling of normal and knockdown DHHC5 cell lines by mass spectrometry.
Citation Format: Hui Tian, Jui-Yun Lu, Chunli Shao, Kenneth Huffman, Ryan Carstens, John D. Minna, Sandra L. Hofmann. Protein palmitoylation in non-small cell lung cancer (NSCLC): DHHC5 palmitoyltransferase as a potential therapeutic target. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4619. doi:10.1158/1538-7445.AM2014-4619
Abstract 4657: Evaluation of genomic profiling in the GALAXY-1 (NCT01348126), a randomized Phase 2b study of ganetespib in combination with docetaxel versus docetaxel alone as second line therapy in patients with advanced NSCLC
Authors: Fennell Dean , Antonov Alexey , Martins Miguel L. , Popat Sanjay , Ramalingam Suresh S. , Spicer James , Vukovic Vojislav M. , El-Hariry Iman , Reichert Vienna , Rosell Rafael 
Published: May 2015

Abstract
Background: Inhibition of Hsp90, a key molecular chaperone required for activation of many oncoproteins, can lead to cancer cell death. Ganetespib (G) is a 2nd generation Hsp90 inhibitor (Hsp90i) that has single agent clinical activity in patients with ALK, KRAS, HER2, and BRAF mutations. G also inhibits pathways implicated in resistance to taxanes, including hypoxia pathways (HIF-1α) as well as cell-cycle and DNA repair pathways. Combination of G with docetaxel (D) has shown synergy in NSCLC xenografts and prolongation of progression-free survival (PFS) and overall survival (OS) of patients with NSCLC adenocarcinoma in interim analyses of the GALAXY-1 trial. Methods: Patients enrolled in GALAXY-1 (n=253) receive D 75 mg/m2 on D1 of a 3-week treatment cycle; combination arm patients receive G 150 mg/m2 on D1 and D15 in addition. The co-primary endpoints are PFS in patients with elevated baseline level of serum LDH and PFS in the mutant KRAS population. PFS and OS in all adenocarcinoma patients are key secondary endpoints. Genomic profiling using Affymetrix Oncoscan™ was performed on archival tissues obtained at baseline, with the goal of determining biomarkers predictive of ganetespib activity
Results: Tumor tissue samples from 65 patients and 26 matched normal tissues were processed on the Affymetrix OncoScan™ FFPE Express 2.0 Services assay. The OncoScan™ FFPE Express 2.0 assay contains 332941 copy number probes. After removing samples with average call rates lower than 90%, 296522 markers on chromosome 1-22 were selected for copy number analyses. For preliminary evaluation of interactions between copy number aberrations and treatment response in the G arm, a genome scale Kaplan-Meier Estimates PFS analysis at each of 296522 markers was performed.
Conclusions: Genomic profiling using OncoScan™ is utilized in the GALAXY-1 trial to identify biomarkers of response/resistance to ganetespib administered in combination with docetaxel. Complete analyses will be presented at the meeting.
Note: This abstract was not presented at the meeting.
Citation Format: Dean Fennell, Alexey Antonov, Miguel L. Martins, Sanjay Popat, Suresh S. Ramalingam, James Spicer, Vojislav M. Vukovic, Iman El-Hariry, Vienna Reichert, Rafael Rosell. Evaluation of genomic profiling in the GALAXY-1 (NCT01348126), a randomized Phase 2b study of ganetespib in combination with docetaxel versus docetaxel alone as second line therapy in patients with advanced NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4657. doi:10.1158/1538-7445.AM2014-4657
Abstract 4660: Temporal interrogation of EGFR signaling in head and neck cancer reveals highly distinct phosphorylation waves for individual EGFR inhibitors
Authors: Iyer Gopal 
Published: May 2015

Abstract
Targeting the epidermal growth factor receptor (EGFR/HER) family is an effective target for cancer therapeutics with thousands of cancer patients treated annually with EGFR inhibitors. However, we are only beginning to appreciate the rapid and dynamic signaling impact of various EGFR inhibitors on cancer cell phosphorylation events. The purpose of this study was to characterize the temporal phosphoprotein kinetics in head and neck cancer cells treated with the anti-EGFR antibodies cetuximab and Sym004. For the first time, perturbation data were generated using reverse phase protein array probed with 183 phosphorylated proteins involved in various signaling pathways at 11 different time points starting as early as 5 min and up to 24 hours. A novel signaling module comprised of phospho-ATM at Ser-1981, p-53(Ser15), p-IkB-α (Ser32/36) and p-Bad (Ser112) was found to be highly upregulated following exposure to Sym004. Concomitantly, high resolution imaging also revealed rapid EGFR degradation and increased endosomal trafficking with Sym004 treatment. Correlation matrix on a temporal scale revealed distinct network topologies suggesting that phosphorylation occurs in distinct waves over time. These response patterns were highly distinct when comparing cetuximab with Sym004. Using this platform, we are able to quantify the strength of various signaling networks triggered by EGFR inhibition and are able to model new pathways. These findings may have significant implications for developing more personalized treatment strategies including logical combination with other molecular target inhibitors.
Note: This abstract was not presented at the meeting.
Citation Format: Gopal Iyer. Temporal interrogation of EGFR signaling in head and neck cancer reveals highly distinct phosphorylation waves for individual EGFR inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4660. doi:10.1158/1538-7445.AM2014-4660
Abstract 4678: Application of the EGFR in squamous lung cancer and its relationship between p63
Authors: Han Yiping , Wang Bibo , Huang Ling , Qiang Li 
Published: May 2015

Abstract
OBJECTIVE: Epidermal growth factor receptor (EGFR) mutations are rarely found in squamous cell carcinoma (SQC).
METHODS: Between J February 2010 and March 2013, we investigated the incidence of EGFR activating mutations in SQC of the lung using the automated direct sequencing of polymerase chain reaction products method. The efficacies of formal therapy, observation, targeting therapy (EGFR-tyrosine kinase inhibitors [TKIs]) were retrospectively evaluated in patients with EGFR-mutated SQC. Further pathologic analyses were performed using immunohistochemistry.
RESULTS: Sixteen of the 282 patients with SQC (5.67%) had EGFR mutations, including exon 19 deletion (7 of 16 patients, 44%), L858R point mutation in exon 21 (9 of 16, 56%). The patients' median progression-free survival (PFS) and median overall survival (OS) in formal therapy, observation and targeting therapy were 6.28 and 9.03, 5.23 and 6.17, and 4.20 and 10.57 months. The median OS of 4 EGFR-mutated patients received p63 (partly +) was 11.28 months (95% confidence interval [CI], 6.33-16.23months) verse that of 11 EGFR-mutated patients received p63 (+) was 3.57 months (95%CI, 1.75- 5.39 months) (p=0.039).
CONCLUSION: EGFR-TKIs for EGFR-mutated SQC are generally inferior to that for EGFR-mutated ADC. Chemotherapy or radiation therapy seemed to be less inferior to TKI therapy considering the PFS and OS results and the economy when patients are in good status. Patients presenting partly + of p63 had longer OS than p63 + patients. EGFR and p63 might be two separate factors which affected the proliferation of squamous tumor cells and result remained to be confirmed by large samples.
KEYWORDS: squamous lung cancer, SQC,epidermal growth factor receptor, EGFR, P63
Note: This abstract was not presented at the meeting.
Citation Format: Yiping Han, Bibo Wang, Ling Huang, Li Qiang. Application of the EGFR in squamous lung cancer and its relationship between p63. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4678. doi:10.1158/1538-7445.AM2014-4678
Abstract 4691: Overactivation of poly (ADP-ribose) polymerase (PARP) in localised non-small cell lung cancer (NSCLC) predicts dismal prognosis
Authors: Michels Judith , Goubar Aïcha , Adam Julien , Galluzzi Lorenzo , Olaussen Ken André , Robin Angélique , Girard Philippe , Kremer Isabelle , Castedo Maria , Soria Jean-Charles , Kroemer Guido 
Published: May 2015

Abstract
Recent studies underscore the general cytoprotective role of PARP1 and PAR in response to multiple extrinsic and intrinsic stress signals. Moreover, elevated levels of PARP have been correlated with increased tumor aggressiveness in breast cancer. Based on these premises, we decided to test whether PARP/PAR levels would be associated with prognosis in a cohort of localised NSCLC patients. Our cohort of patients underwent surgery from 1994 to 2002 and did not receive any chemotherapy. In these tumors, expression of PARP enzyme and the presence of its product, PAR, exhibited a significant, though not absolute, correlation, as determined by immunohistochemistry. The staining of PAR and PARP was almost exclusively nuclear, though highly variable in its intensity. Ninety-two NSCLC specimens were scored on a continuous scale of 0-300 and patients were stratified (separated by the median) into PAR low, PAR high, PARP low and PARP high groups. Tumor-infiltrating lymphocytes (which manifest high PARP and PAR levels) were used as an internal positive control of the staining procedure. Of note, among PARP low tumors, 32.5% were PAR high, indicating that low PARP protein levels do not preclude a high enzymatic activity. While high PAR levels had a significant negative impact on both disease-free (DFS) and overall survival (OS) (p=0.02 and 0.01, in univariate and 0.07 and 0.04 in multivariate analysis respectively), PARP expression did not correlate with either of these outcomes. We could validate PAR as a negative prognostic biomarker in a second cohort of 136 patients operated from 2002 to 2006. Altogether, these results identify high PAR levels as a biomarker of dismal prognosis in NSCLC.
Citation Format: Judith Michels, Aïcha Goubar, Julien Adam, Lorenzo Galluzzi, Ken André Olaussen, Angélique Robin, Philippe Girard, Isabelle Kremer, Maria Castedo, Jean-Charles Soria, Guido Kroemer. Overactivation of poly (ADP-ribose) polymerase (PARP) in localised non-small cell lung cancer (NSCLC) predicts dismal prognosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4691. doi:10.1158/1538-7445.AM2014-4691
Abstract 4721: Polymorphisms in cancer-related genes and survival in early stage non-small cell lung cancer
Authors: Lee Shin Yup , Choi Yi Young , Jeon Hyo-Sung , Choi Jin Eun , Kang Hyo-Gyoung , Yoo Seung Soo , Lee Eung Bae , Lee Won Kee , Lee Jaehee , Cha Seung Ick , Kim Chang H. , Son Ji Woong , Park Jae Yong 
Published: May 2015

Abstract
Background: This study was conducted to identify genetic polymorphisms associated with the prognosis of patients with early stage non-small cell lung cancer (NSCLC).
Materials and Methods: We genotyped 1,969 potentially functional single nucleotide polymorphisms (SNPs) of 1,151 genes using the Affymetrix custom-made GeneChip, which were related to the development and progression of cancer, in 166 NSCLC patients who underwent curative surgical resection. A replication study was performed on an independent cohort of 626 patients.
Results: Fifty six SNPs which were associated with both overall survival (OS) and disease-free survival (DFS) with log-rank P values lower than 0.05 in a discovery set were selected for validation. Among the 56 SNPs, five SNPs (guanine nucleotide binding protein, beta polypeptide 2-like 1 [GNB2L1] rs1279736C&gt;A and rs3756585T&gt;G, complement component 3 [C3] rs2287845T&gt;C, p300/CBP-associated factor [PCAF] rs17006625A&gt;G, and pericentriolar material 1 [PCM1] rs17691523C&gt;G) were found to be significantly associated with survival outcomes in the same direction as the discovery set. In combined analysis, the rs1279736C&gt;A and s3756585T&gt;G were most significantly associated with OS and DFS in multivariate analysis (P for OS = 4x10-5 and 7x10-5, respectively; and P for DFS = 0.003, both; under a codominant model).
Conclusions: We identified five SNPs as markers for prognosis of patients with surgically resected NSCLC.
Citation Format: Shin Yup Lee, Yi Young Choi, Hyo-Sung Jeon, Jin Eun Choi, Hyo-Gyoung Kang, Seung Soo Yoo, Eung Bae Lee, Won Kee Lee, Jaehee Lee, Seung Ick Cha, Chang Ho Kim, Ji Woong Son, Jae Yong Park. Polymorphisms in cancer-related genes and survival in early stage non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4721. doi:10.1158/1538-7445.AM2014-4721
Abstract 4776: PDK1-dependent activation of AGC kinases is an absolute requirement for AKT oncogenic activity
Authors: Orlacchio Arturo , Arciuch Valeria Antico , Cristofano Antonio Di 
Published: May 2015

Abstract
The PI3K signaling cascade is frequently activated in human cancer, and AKT is commonly considered its major transforming conduit. Thus, PI3K and AKT represent relevant targets for therapeutic purposes. However, the many essential of roles played by this pathway in normal cells poses the problem of reaching therapeutic efficacy without harming healthy tissues. In principle, it would be ideal to target only molecules directly involved in the transformation process, thus reducing the toxicity associated with wide-range inhibitors.
PDK1 plays a key role in the PI3K cascade, directly activating AKT. In addition, PDK1 possesses a substrate docking site named “PIF pocket” that is required to phosphorylate and activate members of the AGC kinase family, including S6K, PKC, SGK, and RSK.
Mice in which the PI3K pathway is constitutively activated in the thyroid epithelium through loss of Pten are born with thyroid hyperplasia that progresses to invasive and metastatic follicular carcinoma, a process that is accelerated by the simultaneous loss of p27 or p53, and by Ras or Braf activation.
Using in vivo as well as ex vivo and in vitro genetic and pharmacological approaches, we now show that although Akt activation is necessary, it is not sufficient to transform thyroid epithelial cells. Concomitant activation of Pdk1-dependent pathways is absolutely required to develop neoplastic lesions in vivo, and to induce cell proliferation ex vivo. Pten mutants develop adenomas and carcinomas by one year of age. Strikingly, complete rescue of this phenotype is observed in compound mutants in which, in addition to thyroid-specific Pten loss, the PIF-pocket of Pdk1 has been genetically disrupted, maintaining constitutive activation of Akt and mTor, but not of PIF-pocket dependent AGC kinases.
We also show that the transcription factor STAT3 represents a key mediator of this essential Pdk1-dependent pathway: STAT3 phosphorylation is increased in Pten mutants, and abolished in compound mutants. Furthermore, genetic and pharmacological inhibition of STAT3 drastically impairs cell proliferation in vitro and rescues the hyperplastic phenotype of Pten mutant mice in vivo.
Thus, we have identified an essential and druggable signaling cascade that critically cooperates with AKT activation to transform thyroid epithelial cells.
Citation Format: Arturo Orlacchio, Valeria Antico Arciuch, Antonio Di Cristofano. PDK1-dependent activation of AGC kinases is an absolute requirement for AKT oncogenic activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4776. doi:10.1158/1538-7445.AM2014-4776