PMID: 28507002 (Cell)   Terms: in vivo, xenograft, mice, tumor xenografts
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0		Neuregulin 1 Allosterically Enhances the Antitumor Effects of the Noncompeting Anti-HER3 Antibody 9F7-F11 by Increasing Its Binding to HER3 .
1		Exploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregulin ( NRG1 ; HER3 ligand ) expression at tumor sites is a predictive biomarker of anti-HER3 antibody efficacy in cancer .
2		We hypothesized that in NRG1-expressing tumors , where the ligand is present before antibody treatment , anti-HER3 antibodies that do not compete with NRG1 for receptor binding have a higher receptor -neutralizing action than antibodies competing with the ligand for binding to HER3 .
3		Using time-resolved-fluorescence energy transfer ( TR-FRET ) , we demonstrated that in the presence of recombinant NRG1 , binding of 9F7-F11 ( a nonligand -competing anti-HER3 antibody ) to HER3 is increased , whereas that of ligand -competing anti-HER3 antibodies ( H4B-121 , U3-1287 , Ab#6 , Mab205102 , and MOR09825 ) is decreased .
4		Moreover , 9F7-F11 showed higher efficacy than antibodies that compete with the ligand for binding to HER3 .
5		Specifically , 9F7-F11 inhibition of cell proliferation and of HER3/AKT/ERK1/2 phosphorylation as well as 9F7-F11 -dependent cell -mediated cytotoxicity were higher in cancer cells preincubated with recombinant NRG1 compared with cells directly exposed to the anti-HER3 antibody .
6		This translated in vivo into enhanced growth inhibition of NRG1-expressing BxPC3 pancreatic , A549 lung , and HCC-1806 breast cell tumor xenografts in mice treated with 9F7-F11 compared with H4B-121 .
7		Conversely , both antibodies had similar antitumor effect in NRG1-negative HPAC pancreatic carcinoma cells .
8		In conclusion , the allosteric modulator 9F7-F11 shows increased anticancer effectiveness in the presence of NRG1 and thus represents a novel treatment strategy for NRG1-addicted tumors .
9		Mol Cancer Ther ; 16(7) ; 1312-23 .
10		(c) 2017 AACR .

PMID: 27259358 (Cell)   Terms:
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0		Resolution of Novel Pancreatic Ductal Adenocarcinoma Subtypes by Global Phosphotyrosine Profiling .
1		Comprehensive characterization of signaling in pancreatic ductal adenocarcinoma ( PDAC ) promises to enhance our understanding of the molecular aberrations driving this devastating disease , and may identify novel therapeutic targets as well as biomarkers that enable stratification of patients for optimal therapy .
2		Here , we use immunoaffinity-coupled high-resolution mass spectrometry to characterize global tyrosine phosphorylation patterns across two large panels of human PDAC cell lines : the ATCC series ( 19 cell lines ) and TKCC series ( 17 cell lines ) .
3		This resulted in the identification and quantification of over 1800 class 1 tyrosine phosphorylation sites and the consistent segregation of both PDAC cell line series into three subtypes with distinct tyrosine phosphorylation profiles .
4		Subtype-selective signaling networks were characterized by identification of subtype-enriched phosphosites together with pathway and network analyses .
5		This revealed that the three subtypes characteristic of the ATCC series were associated with perturbations in signaling networks associated with cell - cell adhesion and epithelial-mesenchyme transition , mRNA metabolism , and receptor tyrosine kinase ( RTK ) signaling , respectively .
6		Specifically , the third subtype exhibited enhanced tyrosine phosphorylation of multiple RTKs including the EGFR , ERBB3 and MET .
7		Interestingly , a similar RTK-enriched subtype was identified in the TKCC series , and 'classifier' sites for each series identified using Random Forest models were able to predict the subtypes of the alternate series with high accuracy , highlighting the conservation of the three subtypes across the two series .
8		Finally , RTK-enriched cell lines from both series exhibited enhanced sensitivity to the small molecule EGFR inhibitor erlotinib , indicating that their phosphosignature may provide a predictive biomarker for response to this targeted therapy .
9		These studies highlight how resolution of subtype-selective signaling networks can provide a novel taxonomy for particular cancers , and provide insights into PDAC biology that can be exploited for improved patient management .

PMID: 26668065 (Patient)   Terms: in vivo
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0		Afatinib , an Irreversible EGFR Family Inhibitor , Shows Activity Toward Pancreatic Cancer Cells , Alone and in Combination with Radiotherapy , Independent of KRAS Status .
1		BACKGROUND :
2		Pancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent deregulation of the epidermal growth factor receptor ( EGFR ) and other EGFR family members such as HER2/ErbB2 .
3		The EGFR inhibitor erlotinib is approved for treatment of pancreatic cancer , but has shown modest activity in most patients .
4		OBJECTIVE :
5		Here we investigated the activity of afatinib , a second-generation irreversible pan-EGFR family kinase inhibitor , alone or in combination with ionizing radiation , toward pancreatic cancer cells .
6		METHODS :
7		The influence of afatinib on cell proliferation , cell cycle distribution , clonogenic survival , nuclear fragmentation , ploidy , and centrosome amplification following irradiation was determined .
8		Expression and phosphorylation of HER receptors , Akt , DNA-PKcs , and ERK1/2 was characterized by Western blot analysis .
9		RESULTS :
10		Afatinib was growth-inhibitory for all three cell lines but cytotoxic only toward BxPC3 ( KRAS ( wt ) ) and Capan-2 ( KRAS ( mut ) ) cells , both of which express high levels of EGFR , HER2 , and HER3 receptors .
11		Afatinib increased the radiosensitivity of BxPC3 and Capan-2 cells , prevented the radio-induced phosphorylation of Akt , and induced mitotic catastrophe following irradiation .
12		In comparison , Panc-1 cells ( KRAS ( mut ) ) expressing low levels of EGFR family receptors were resistant to afatinib-induced radiosensitization .
13		LIMITATIONS :
14		These results must be confirmed in vivo .
15		CONCLUSIONS :
16		Afatinib showed cytotoxic and radiosensitizing effects toward a subset of pancreatic cancer cells which was closely correlated with expression of EGFR , HER2 , and HER3 receptors , but not with KRAS status .

PMID: 26460961 (None)   Terms: In vivo, Ex vivo, in vivo
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0		In vivo imaging of therapy response to a novel pan-HER antibody mixture using FDG and FLT positron emission tomography .
1		PURPOSE :
2		Overexpression of the human epidermal growth factor receptor ( HER ) family and their ligands plays an important role in many cancers .
3		Targeting multiple members of the HER family simultaneously may increase the therapeutic efficacy .
4		Here , we report the ability to image the therapeutic response obtained by targeting HER family members individually or simultaneously using the novel monoclonal antibody ( mAb ) mixture Pan-HER .
5		EXPERIMENTAL DESIGN AND RESULTS :
6		Mice with subcutaneous BxPC-3 pancreatic adenocarcinomas were divided into five groups receiving vehicle or mAb mixtures directed against either EGFR (HER1) , HER2 , HER3 or all three receptors combined by Pan-HER .
7		Small animal positron emission tomography/computed tomography ( PET/CT ) with 2'-deoxy-2'-[ ( 18 ) F]fluoro-D-glucose ( FDG ) and 3'-deoxy-3'-[ ( 18 ) F]fluorothymidine ( FLT ) was performed at baseline and at day 1 or 2 after initiation of therapy .
8		Changes in tumor uptake of tracers were quantified and compared to reduction in tumor size .
9		Imaging results were further validated by immunohistochemistry and qPCR .
10		Mean FDG and FLT uptake in the Pan-HER treated group decreased by 19 +/- 4.3% and 24 +/- 3.1% , respectively .
11		The early change in FDG and FLT uptake correlated with tumor growth at day 23 relative to day 0 .
12		Ex vivo molecular analyses of markers associated with the mechanisms of FDG and FLT uptake confirmed the in vivo imaging results .
13		CONCLUSIONS :
14		Taken together , the study supports the use of FDG and FLT as imaging biomarkers of early response to Pan-HER therapy .
15		FDG and FLT PET/CT imaging should be considered as imaging biomarkers in clinical evaluation of the Pan-HER mAb mixture .

PMID: 26287187 (Patient)   Terms:
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0		Pyrosequencing-Based Assays for Rapid Detection of HER2 and HER3 Mutations in Clinical Samples Uncover an E332E Mutation Affecting HER3 in Retroperitoneal Leiomyosarcoma .
1		Mutations in Human Epidermal Growth Factor Receptors ( HER ) are associated with poor prognosis of several types of solid tumors .
2		Although HER-mutation detection methods are currently available , such as Next-Generation Sequencing ( NGS ) , alternative pyrosequencing allow the rapid characterization of specific mutations .
3		We developed specific PCR-based pyrosequencing assays for identification of most prevalent HER2 and HER3 mutations , including S310F/Y , R678Q , L755M/P/S/W , V777A/L/M , 774-776 insertion , and V842I mutations in HER2 , as well as M91I , V104M/L , D297N/V/Y , and E332E/K mutations in HER3 .
4	Μ	We tested 85 Formalin Fixed and Paraffin Embbeded ( FFPE ) samples and we detected three HER2-V842I mutations in colorectal carcinoma ( CRC ) , ovarian carcinoma , and pancreatic carcinoma patients , respectively , and a HER2-L755M mutation in a CRC specimen .
5		We also determined the presence of a HER3-E332K mutation in an urothelial carcinoma sample , and two HER3-D297Y mutations , in both gastric adenocarcinoma and CRC specimens .
6	Μ	The D297Y mutation was previously detected in breast and gastric tumors , but not in CRC .
7	Μ	Moreover , we found a not-previously-described HER3-E332E synonymous mutation in a retroperitoneal leiomyosarcoma patient .
8		The pyrosequencing assays presented here allow the detection and characterization of specific HER2 and HER3 mutations .
9		These pyrosequencing assays might be implemented in routine diagnosis for molecular characterization of HER2/HER3 receptors as an alternative to complex NGS approaches .

PMID: 26088450 (Cell)   Terms:
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0	✓	High expression of ErbB3 binding protein 1 ( EBP1 ) predicts poor prognosis of pancreatic ductal adenocarcinoma ( PDAC ) .	GE-REG-RO
1		Recent studies have identified that ErbB3 binding protein 1 ( EBP1 ) is broadly expressed in various cancer tissues and critically involved in plenty of biological processes in this regard .
2		However , the functional role of EBP1 in pancreatic ductal adenocarcinoma ( PDAC ) has never been elucidated .
3		In this study , we found that EBP1 could serve as a prognostic biomarker of PDAC .
4		Western blot analysis revealed that EBP1 was remarkably upregulated in PDAC tissues and cell lines .
5	Μ	Using immunohistochemical analysis , we showed that the expression of EBP1 was correlated with tumor size ( P = 0004 ) , histological differentiation ( P = 0041 ) , and tumor node metastasis ( TNM ) stage ( P = 0000 ) .
6	Μ	Notably , Kaplan-Meier curve showed that high expression of EBP1 predicted significantly worsened prognosis of PDAC patients ( P = 0001 ) .
7		In addition , knockdown of EBP1 expression suppressed PDAC cell proliferation and retarded cell cycle progression .
8		Furthermore , depletion of EBP1 induced the apoptosis of Panc-1 cells .
9		Of great interest , we found that EBP1 interacted with anti-apoptotic protein , Bcl-xL , and promoted its accumulation .
10		In summary , our results suggest that EBP1 is a novel prognostic indicator and potential therapeutic target of PDAC , shedding new insights into the important role of EBP1 in cancer development .

PMID: 25216528 (None)   Terms: in vivo, in vitro, xenograft, mice
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0		HER3 as biomarker and therapeutic target in pancreatic cancer : new insights in pertuzumab therapy in preclinical models .
1		The anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling .
2		As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis , we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer .
3		We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression .
4		HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy .
5		Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane , whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it .
6		Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers .
7		The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells .
8		Finally , HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry .
9	✓	HER3 is essential for pertuzumab efficacy in HER2low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers .	GE-INV-RO
10		Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies .

PMID: 24269963 (Patient)   Terms:
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0		The ErbB/HER family of protein-tyrosine kinases and cancer .
1		The human epidermal growth factor receptor ( EGFR ) family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4) .
2		These receptors consist of a glycosylated extracellular domain , a single hydrophobic transmembrane segment , and an intracellular portion with a juxtamembrane segment , a protein kinase domain , and a carboxyterminal tail .
3		Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor alpha , none bind to ErbB2 , two bind to ErbB3 , and seven ligands bind to ErbB4 .
4		The ErbB proteins function as homo and heterodimers .
5		The heterodimer consisting of ErbB2 , which lacks a ligand , and ErbB3 , which is kinase impaired , is surprisingly the most robust signaling complex of the ErbB family .
6		Growth factor binding to EGFR induces a large conformational change in the extracellular domain , which leads to the exposure of a dimerization arm in domain II of the extracellular segment .
7		Two ligand -EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate .
8		Following ligand binding , EGFR intracellular kinase domains form an asymmetric homodimer that resembles the heterodimer formed by cyclin and cyclin -dependent kinase .
9		The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino - terminal lobe of the receiver kinase thereby leading to its allosteric stimulation .
10		Downstream ErbB signaling modules include the phosphatidylinositol 3-kinase/Akt ( PKB ) pathway , the Ras/Raf/MEK/ERK1/2 pathway , and the phospholipase C ( PLCgamma ) pathway .
11		Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung , breast , stomach , colorectal , head and neck , and pancreatic carcinomas and glioblastoma ( a brain tumor ) .
12		Gefitinib , erlotinib , and afatinib are orally effective protein - kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer .
13		Lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer .
14		Trastuzumab , pertuzumab , and ado-trastuzumab emtansine , which are given intravenously , are monoclonal antibodies that target the extracellular domain and are used for the treatment of ErbB2-positive breast cancer ; ado-trastuzumab emtansine is an antibody - drug conjugate that delivers a cytotoxic drug to cells overexpressing ErbB2 .
15		Cetuximab and panitumumab are monoclonal antibodies that target ErbB1 and are used in the treatment of colorectal cancer .
16		Cancers treated with these targeted drugs eventually become resistant to them .
17		The role of combinations of targeted drugs or targeted drugs with cytotoxic therapies is being explored in an effort to prevent or delay drug resistance in the treatment of these malignancies .

PMID: 23918833 (Cell)   Terms:
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0		Subtype-specific MEK-PI3 kinase feedback as a therapeutic target in pancreatic adenocarcinoma .
1		Mutations in the KRAS oncogene are dominant features in pancreatic ductal adenocarcinoma ( PDA ) .
2		Because KRAS itself is considered "undruggable , " targeting pathways downstream of KRAS are being explored as a rational therapeutic strategy .
3		We investigated the consequences of MAP-ERK kinase ( MEK ) inhibition in a large PDA cell line panel .
4		Inhibition of MEK activated phosphoinositide 3 - kinase in an EGF receptor ( EGFR )- dependent fashion and combinations of MEK and EGFR inhibitors synergistically induced apoptosis .
5		This combinatorial effect was observed in the epithelial but not mesenchymal subtype of PDA .
6	Μ	RNA expression analysis revealed predictors of susceptibility to the combination , including E-cadherin , HER3 , and the miR200-family of microRNAs , whereas expression of the transcription factor ZEB1 was associated with resistance to the drug combination .
7		Knockdown of HER3 in epithelial-type and ZEB1 in mesenchymal-type PDA cell lines resulted in sensitization to the combination of MEK and EGFR inhibitors .
8		Thus , our findings suggest a new , subtype-specific , and personalized therapeutic strategy for pancreatic cancer .

PMID: 22436610 (None)   Terms:
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0		The oncoprotein ErbB3 is endocytosed in the absence of added ligand in a clathrin -dependent manner .
1		The oncoprotein ErbB3 is overexpressed in several human cancers , for example in pancreatic adenocarcinoma and in ovarian cancers , and ErbB3-containing heterodimers have been demonstrated to be potent signaling units in carcinogenesis .
2		This especially applies to ErbB2-ErbB3 and epidermal growth factor receptor ( EGFR ) -ErbB3 heterodimers providing anti-apoptotic signaling .
3		Relatively little is understood about the signaling of EGFR-ErbB3 heterodimers and especially about mechanisms involved in downregulation of ErbB3 from the plasma membrane .
4		This is in contrast to EGFR homodimers , for which trafficking has been extensively characterized .
5		In the present study , we have investigated mechanisms involved in endocytosis of ErbB3 in porcine aortic endothelial cells stably expressing either ErbB3 only or stably expressing ErbB3 and EGFR .
6		Our data show that ErbB3 is endocytosed in the absence of added ligand , independently of its tyrosine phosphorylation state and in a clathrin -dependent manner .
7		Functional EGFR-ErbB3 heterodimers were observed to be formed , and dimerization with ErbB3 was observed to negatively affect endocytosis of the EGFR .

PMID: 21792199 (None)   Terms:
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0		Targeting ErbB3 -mediated stromal-epithelial interactions in pancreatic ductal adenocarcinoma .
1		Gastrointestinal stromal tumours ( GISTs ) are most common in the stomach ( 60-70% ) , followed by small intestine ( 20-25% ) , colon and rectum ( 5% ) , and esophagus ( <5% ) .
2		They are characterized by expression of the transmembrane receptor tyrosine kinase KIT , which is defined by the CD117 antigen and is the product of the kit proto-oncogene .
3		Metastatic risk is based on tumour size and mitotic count .
4		The treatment options have evolved rapidly with the discovery of imatinib ( Gleevec ) that selectively inhibits KIT .
5		Complete resection without tumour rupture remains the mainstay of treatment in patients with localized , resectable disease .
6		Imatinib has been shown to be the first successful systemic therapy for patients with metastatic or unresectable disease and is also currently being tested as an adjuvant therapy after the resection of high risk primary GIST .
7		New blockers of the tyrosine - kinase activity are currently in development in cases of resistance .

PMID: 20647770 (None)   Terms: in vitro, In vivo
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0	✓	ErbB3 expression promotes tumorigenesis in pancreatic adenocarcinoma .	GE-REG-RO
1		Historically , ErbB3 has been overlooked within the ErbB receptor family due to its perceived lack of tyrosine kinase activity .
2		We have previously demonstrated that in pancreatic cancer ErbB3 is the preferred dimerization partner of EGFR , ErbB3 protein expression level directly correlates with the anti-proliferative effect of erlotinib ( an EGFR-specific tyrosine kinase inhibitor ) , and transient knockdown of ErbB3 expression results in acquired resistance to EGFR-targeted therapy .
3		In this study , we develop a stable isogenic model of ErbB3 expression in an attempt to decipher ErbB3 's true contribution to pancreatic cancer tumorigenesis and to examine how this receptor affects cellular sensitivity to EGFR-targeted therapy .
4		Analysis of the EGFR-ErbB3 heterodimer demonstrates that ligand -induced PI3K-AKT signaling is limited to ErbB3-expressing cells and that this signaling cascade can be partially abrogated by inhibiting EGFR function with erlotinib .
5		Using our model of exogenous ErbB3 expression we showed a direct relationship between ErbB3 protein levels and increased pancreatic cancer cell proliferation in vitro .
6		In vivo , LONGTOKEN and displayed increased sensitivity to EGFR-targeted therapy .
7		In pancreatic cancer , ErbB3 appears to be critically involved in EGFR signaling as evidenced by its profound effect on cellular proliferation and its ability to influence response to EGFR-targeted therapy .

PMID: 19304440 (Patient)   Terms:
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0		HER-family gene amplification and expression in resected pancreatic cancer .
1		AIMS :
2		Despite surgical resection , pancreatic cancer carries a poor prognosis .
3		In search for new molecular therapeutic targets , we investigated the expression of the HER-family and gene amplification of HER-2 in pancreatic adenocarcinomas of different stages .
4		METHODS :
5		Tissue of 45 resected patients was analyzed for all HER-family 1-4 expression by immunohistochemistry and HER-2 gene amplification was assessed by multiplex ligation -dependent probe amplification and chromogenic in situ hybridization .
6		The type of surgery , location , stage and grade of the tumor , as well as involvement of the resection margins were correlated with HER-expressions and univariate and multivariate survival analysis performed .
7		RESULTS :
8		Normal pancreatic tissue lacked HER1-2 expression , but did show HER3-4 expression .
9	Μ	In cancers , no membranous overexpression of HER-1 and HER-2 was seen nor gene amplification of HER-2 found .
10		HER-3 , HER-4 is physiologically expressed in the normal pancreas and loss of cytoplasmic HER-3 and HER-4 expression was seen in 33/45 ( 73% ) and 8/45 ( 18% ) of pancreatic cancers .
11		Cytoplasmic HER-3 expression decreased from early to late stage ( p = 005 ) .
12	✓	HER-4 expression was not associated with survival , stage or tumor grade .	GE-ASS-RO
13		There were no statistically significant differences in HER1-4 expression between the papilla of Vater ( n = 13 ) and non-papilla cancers ( n = 32 ) .
14		Multivariate survival analysis showed only stage to be of independent prognostic value ( p = 0015 ) .
15		CONCLUSIONS :
16		HER-1 and HER-2 are not overexpressed in pancreatic cancers .
17	Μ	HER-3 and HER-4 are expressed in the normal pancreas but expression is lost in pancreatic cancer .
18		HER-targeted therapy in pancreatic cancer is not supported by HER-expression of the tumor .

PMID: 18483264 (Cell)   Terms:
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0		Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells .
1		Receptor tyrosine kinases ( RTK ) are therapeutic targets for the treatment of malignancy .
2		However , tumor cells develop resistance to targeted therapies through the activation of parallel signaling cascades .
3		Recent evidence has shown that redundant or compensatory survival signals responsible for resistance are initiated by nontargeted glycoprotein RTKs coexpressed by the cell .
4		We hypothesized that disrupting specific functions of the posttranslational machinery of the secretory pathway would be an effective strategy to target both primary and redundant RTK signaling .
5		Using the N-linked glycosylation inhibitor , tunicamycin , we show that expression levels of several RTKS ( EGFR , ErbB2 , ErbB3 , and IGF-IR ) are exquisitely sensitive to inhibition of N-linked glycosylation .
6		Disrupting this synthetic process reduces both cellular protein levels and receptor activity in tumor cells through retention of the receptors in the endoplasmic reticulum/Golgi compartments .
7		Using U251 glioma and BXPC3 pancreatic adenocarcinoma cell lines , two cell lines resistant to epidermal growth factor receptor -targeted therapies , we show that inhibiting N-linked glycosylation markedly reduces RTK signaling through Akt and radiosensitizes tumor cells .
8		In comparison , experiments in nontransformed cells showed neither a reduction in RTK -dependent signaling nor an enhancement in radiosensitivity , suggesting the potential for a therapeutic ratio between tumors and normal tissues .
9		This study provides evidence that enzymatic steps regulating N-linked glycosylation are novel targets for developing approaches to sensitize tumor cells to cytotoxic therapies .

PMID: 17096356 (Cell)   Terms: In vivo
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0		Expression and differential signaling of heregulins in pancreatic cancer cells .
1		The EGF family of ligands and receptors plays an important role in the pathogenesis of pancreatic ductal adenocarcinoma ( PDAC ) and contributes to its aggressiveness .
2		A number of molecular approaches have been developed to block these pathways , and studies have already proven the clinical benefit of this concept in PDAC .
3		In the present study , we sought to determine the potential role of heregulins ( HRGs ) , a family of EGF-like growth factors , in PDAC .
4		Quantitative RT-PCR analysis revealed that HRGs as well as its signaling ErbB receptors were present in 4 of 4 human pancreatic cancer cell lines ( PCCL ) .
5		HRG-beta1 stimulated the growth of 3 of 4 PCCL , whereas HRG-alpha1 inhibited cell growth in 3 of 4 cell lines .
6		Responses towards HRGs could in part be predicted by ErbB2 and ErbB3 expression levels .
7		HRGs induced phosphorylation of different ErbB receptors as well as activation of MAPK , p38MAPK , JNK and PI3K in a cell - and ligand -specific manner .
8		In vivo , HRG was upregulated in pancreatic cancer tissues and localized predominantly in the cancer cells .
9		High HRG-beta levels but not HRG-alpha levels were associated with decreased patient survival .
10		In conclusion , HRG is expressed by pancreatic cancer cells and influences pancreatic cancer cell growth and patient survival .

PMID: 15585383 (Cell)   Terms: in vivo, in vitro
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0		Mechanisms of resistance to Erbitux ( anti-epidermal growth factor receptor ) combination therapy in pancreatic adenocarcinoma cells .
1		We previously demonstrated that pancreatic adenocarcinoma BxPC-3 xenografts display resistance to treatment with Erbitux , gemcitabine , and radiation , whereas MIA PaCa-2 xenografts are highly sensitive to the same therapy .
2		Here , we elucidate in vitro mechanisms that may explain the observed differential response of epidermal growth factor receptor ( EGFR ) expressing pancreatic adenocarcinoma xenografts to Erbitux-based combination therapy in vivo .
3		MIA PaCa-2 and BxPC-3 protein lysates were probed with antibodies to EGFR , ErbB2 , ErbB3 , and ErbB4 .
4		Constitutive ErbB3 activity was visualized by immunoblot analysis using anti-phosphotyrosine antibodies and receptor -specific immunoprecipitates .
5		erbB2 and erbB3 gene expression in both cell lines was quantified with real-time polymerase chain reaction .
6		Erbitux-induced internalization of EGFR was determined by flow cytometry following Erbitux treatment for different incubation times at 0 degrees C and 37 degrees C .
7		MIA PaCa-2 and BxPC-3 protein extracts were also probed with anti-phospho-mitogen -activated protein kinase antibody after stimulation with EGF and in the presence of Erbitux .
8		Although both cell lines expressed EGFR and ErbB2 protein , ErbB3 protein was selectively expressed by BxPC-3 cells , where it also showed evidence of constitutive phosphorylation .
9		There was a 10-fold increase of erbB3 transcript levels in BxPC-3 cells compared with MIA PaCa-2 .
10		ErbB4 protein was not detectable in either cell line .
11		Erbitux mediated EGFR internalization in MIA PaCa-2 cells after 2 hours of incubation , whereas it did not promote EGFR internalization in BxPC-3 cells .
12		Likewise , EGF -dependent phosphorylation of MAPK p44/42 was blocked by Erbitux treatment in MIA PaCa-2 but not BxPC-3 cells .
13		Erbitux selectively interfered with EGF -induced MAPK activation in MIA PaCa-2 but not BxPC-3 cells .
14		Persistent MAPK activation and impaired in vitro internalization of EGFR by BxPC-3 pancreatic cancer cells may be due to constitutive ErbB3 signaling , facilitated by heterodimerization with EGFR , which may explain resistance to Erbitux-based combination therapy in vivo .

PMID: 11102889 (Patient)   Terms:
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0	✓	K-ras oncogene subtype mutations are associated with survival but not expression of p53 , p16 ( INK4A ) , p21 ( WAF-1 ) , cyclin D1 , erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma .	GM-ASS-RO
1		Previous studies of molecular prognostic markers following resection for exocrine pancreatic cancer have produced conflicting results .
2		Our aim was to undertake a comprehensive analysis of potentially useful molecular markers in a large , multicentre patient population and to compare these markers with standard pathological prognostic variables .
3		Formalin-fixed , paraffin-embedded specimens of pancreatic ductal adenocarcinoma were analysed from 157 patients [100 men and 57 women with a median ( range ) age of 60 ( 33-77 ) years] who had undergone pancreatectomy .
4	Μ	Immunohistochemistry was used to detect expression of p16 ( INK4 ) , p53 , p21 ( WAF1 ) , cyclin D1 , erbB-2 and erbB-3 .
5	Μ	Mutations in codons 12 and 13 of the K-ras oncogene were detected by SSCP and sequencing following DNA extraction and amplification by PCR .
6		The median ( range ) survival post-resection was 12.5 ( 3-83 ) months .
7	Μ	Abnormalities of p16 ( INK4 ) , p53 , p21 ( WAF1 ) , cyclin D1 , erbB-2 and erbB-3 expression were found in 87% , 41% , 75% , 72% , 33% and 57% of cases , respectively .
8		There was no significant correlation between expression of any of these markers and patient survival .
9	Μ	K-ras mutations were found in 73 ( 75% ) of 97 cases with amplifiable DNA .
10		The presence of K-ras mutation alone did not correlate with survival , but there were significant differences in survival according to the type of K-ras mutation ( p = 00007 ) .
11	Μ	Reduced survival was found in patients with GaT , cGT and GcT K-ras mutations compared to GtT , aGT and GaC mutations .
12	✓	In conclusion , survival was associated with type of K-ras mutation but not expression of p16 ( INK4 ) , p53 , p21 ( WAF1 ) , cyclin D1 , erbB-2 and erbB-3 .	RO-ASS-GM

PMID: 8834768 (None)   Terms:
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0		Pancreatic cancer : the potential clinical relevance of alterations in growth factors and their receptors .
1		Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers .
2		In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas .
3		Overexpression of growth factor receptors ( EGF receptor , c-erbB2 , c-erbB3 , TGF beta receptor I-III ) , growth factors ( EGF , TGF alpha , TGF beta-1-3 , aFGF , bFGF ) , adhesion molecules ( ICAM-1 , ELAM-1 ) and gene mutations ( p53 , K-ras , DCC , APC ) are present in a significant number of these tumors .
4		These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection .

PMID: 9815939 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0	✓	Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression .	GE-ASS-RO
1		The erbB-3 gene encodes a transmembrane protein that is related to the epidermal growth factor ( EGF ) receptor and erbB-2 .
2		We compared erbB-3 expression in the normal human pancreas , human pancreatic carcinomas , and cultured human pancreatic cancer cell lines .
3		Northern blot analysis of total RNA revealed the anticipated 6.2-kb mRNA transcript in all 19 normal pancreatic samples .
4		In 17 of 27 pancreatic cancers , there was a 6.7-fold increase ( P <0001 ) in erbB-3 mRNA levels .
5	Μ	Southern blot analysis did not reveal erbB-3 gene amplification .
6		Four of six pancreatic cancer cell lines exhibited the 6.2-kb erbB-3 mRNA transcript , and all four cell lines coexpressed the epidermal growth factor receptor and erbB-2 .
7		Using a highly specific antibody , we determined that faint to moderate erbB-3 immunoreactivity was present in the ductal cells in the normal pancreas .
8		In 47% ( 27/58 ) of the pancreatic cancers , there were many cancer cells with intense erbB-3 immunostaining .
9		The presence of erbB-3 in the cancer cells was associated with advanced tumor stage and shorter survival postoperatively .
10	✓	These data indicate that a significant proportion of human pancreatic cancers overexpress erbB-3 , and that erbB-3 may contribute to disease progression in this disorder .	GE-ASS-RO, GE-INV-RO

PMID: AACR_2013-2446 (Cell)   Terms: in vitro, xenograft, Xenograft, In vitro, In vivo
Sent#	Symbols	Sentence	Mnemonics
0		The effects of dacomitinib ( PF-299 ) on pancreatic ductal adenocarcinoma ( PDAC ) and cancer-associated fibroblasts ( CAFs ) . .
1		Background : PF-299 is an oral irreversible small molecule that is an effective inhibitor of the ErbB pathway , which has been shown to play a critical role in pancreatic ductal adenocarcinoma ( PDAC ) pathogenesis .
2		Indirect activation of Epidermal Growth Factor Receptor ( EGFR ) signaling through ErbB3 heterodimerization and stromal ligand production has been shown to act as an escape mechanism for EGFR directed therapies .
3		This phenomenon may explain the modest clinical benefit of anti-EGFR drugs in PDAC .
4		We have previously shown that CAFs are responsible for the secretion of ErbB pathway ligands .
5		The addition of CAFs to PDAC xenografts improves the tumor modeling and adds testing stringency to novel targeted therapies .
6		We hypothesize that PF-299 inhibition of multiple ErbB receptors results in effective inhibition of PDAC tumor progression .
7		Materials : AsPC-1 , BxPC-3 , C3 , Panc-1 and Panc-1+ErbB3 ( stable ErbB3 transfected cell line ) PDAC cells were treated with different concentrations of PF-299 .
8		PDAC cell proliferation and ErbB signaling was analyzed in vitro .
9		Subcutaneous xenografts were developed using the AsPC-1 and BxPC-3 cell lines alone and in combination with CAFs .
10		CAFs were obtained from surgically resected PDAC tissue .
11		Xenografts were analyzed for tumor growth and tumor-associated ErbB signaling after treatment with PF-299 .
12		Results : In vitro , PF-299 effectively inhibited AsPC-1 , BxPC-3 , C3 , Panc-1 and Panc-1+ErbB3 cell proliferation in a dose -dependent manner ( 1-10 M ) .
13		PF-299 decreased migration of AsPC-1 cells by 54% , while the addition of CAFs ( in co - culture ) increased cell migration by 13% in the PF-299 treated group compared to an increase of 273% in the control group .
14		In vivo , tumor proliferation of AsPC-1 and BxPC-3 xenografts was significantly inhibited by PF-299 treatment ( p = 004 and p = 0002 , respectively ) .
15		Combination of AsPC-1/BxPC-3+CAFs xenografts increased initial tumor size by 22.5% ( p = 017 ) for the AsPC-1 cell line and by 11.6% ( p = 046 ) for the BxPC-3 cell line compared to cells without CAFs .
16		The AsPC-1+CAFs PF-299 treated tumors were 4.1% smaller than placebo treated tumors ( p = 099 ) , while BxPC-3+CAFs PF-299 treated tumor were 26% smaller than the placebo treated group ( p = 005 ) .
17		Immunoblot analysis of AsPC-1/BxPC-3+CAFs xenografts confirmed PF-299 mediated inhibition of both EGFR and ErbB3 mediated signaling .
18		Conclusion : We demonstrated that PF-299 targets multiple ErbB receptors , including ErbB3 .
19		PF-299 significantly inhibited PDAC cell proliferation , migration and tumor progression by targeting EGFR and ErbB3 signaling .
20		CAFs may provide a novel addition to current models by increasing tumor virulence while pan-ErbB receptor targeting may improve therapeutic approaches to PDAC .