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The current study aimed to dissect the impacts and mechanisms of hydroxycamptothecin on breast cancer. Collect conditioned medium from MSCs cells to apply it into the co-culture system of breast cancer cells, which were pre-treated with hydroxycamptothecin. The cell counting kit was employed to measure the proliferation potential of cells, while the phosphorylation degrees of AKT/MAPKrelated proteins were examined via Western blotting. Then the cellular migration was test by transwell. Finally, the transcriptional and translational levels of IL-6 and RANTES in cells were detected by real-time PCR and enzyme-linked immunosorbent assay. HC could remarkably influence the interplay between MSC and breast malignant cells, reduce the MSC-activated migrative behavior of breast malignant cells and impede the capability of MSC to maintain the migration of cancer cells. RANTES and IL-6 exerted a synergistic induction in the migrative feature of breast cancer cells. HC could retard the migrating activities of breast cancer cells via diminishing the RANTES and IL-6 levels. Hydroxycamptothecin could impede the proliferative and migrative activities of MSC, of which the impediment was accompanied by an inhibitory impact on the secretory production of two growth factors IL-6 and RANTES from MSC, thereby enhancing the migration of breast malignant cells.

Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors.

Background Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatment for advanced non-small cell lung cancer (NSCLC). However, the emergence of EGFR-TKIs resistance poses a big challenge to the treatment. Although several resistant mutations have been identified, our understanding of the mechanisms underlying acquired EGFR-TKIs resistance remains incomplete. This study aimed to identify novel mutations and mechanisms that could contribute to acquired EGFR-TKIs resistance in EGFR mutated NSCLC cells. Methods Erlotinib resistant cells (HCC827/ER cells) were generated from the EGFR mutated NSCLC cell line HCC827, and whole-exome sequencing was performed to identify gene mutations in HCC827/ER cells. The Spred-3 expression was determined using quantitative real-time PCR (qPCR) and Western blotting assays, and the p-p44/42, p44/42, p-Akt and Akt expression was determined using Western blotting. The half maximal inhibitory concentration (IC50 value) was measured using the MTS assay, and cell migration was detected with a Transwell migration assay. Results Whole-exome sequencing identified deletion mutation c.120delG at exon 1 of the Spred-3 gene, resulting in a p.E40fs change in amino acid, in HCC827/ER cells. The Spred-3 expression was much reduced in HCC827/ER cells as compared to the HCC827 cells at both mRNA and protein levels. Knocking out Spred-3 in HCC827 cells using CRISPR/Cas9 increased erlotinib resistance and cell migration, while overexpressing Spred-3 in HCC827/ER cells using a cDNA construct reduced erlotinib resistance and cell migration. We also showed the Ras/Raf/MAPK pathway was activated in HCC827/ER cells, and inhibiting ERK1/2 in HCC827/Spred-3-sgRNA cells resulted in reduced erlotinib resistance and cell migration. Conclusions The results of this study indicate that a loss-of-function mutation in Spred-3 resulted in activation of the Ras/Raf/MAPK pathway that confers resistance to EGFR-TKIs in NSCLC cells harboring an EGFR mutation.

Rationale: Glioblastoma multiforme (GBM) almost invariably gain invasive phenotype with limited therapeutic strategy and ill-defined mechanism. By studying the aberrant expression landscape of gliomas, we find significant up-regulation of p-MAPK level in GBM and a potent independent prognostic marker for overall survival. DHHC family was generally expressed in glioma and closely related to the activation of MAPK signaling pathway, but its role and clinical significance in GBM development and malignant progression are yet to be determined. Method: Bioinformatics analysis, western blotting and immunohistochemistry (IHC) were performed to detect the expression of ZDHHC17 in GBM. The biological function of ZDHHC17 was demonstrated by a series of in vitro and in vivo experiments. Pharmacological treatment, flow cytometry, Transwell migration assay, Co- Immunoprecipitation and GST pulldown were carried out to demonstrate the potential mechanisms of ZDHHC17. Results: ZDHHC17 is up-regulated and coordinated with MAPK activation in GBM. Mechanistically, ZDHHC17 interacts with MAP2K4 and p38/JNK to build a signaling module for MAPK activation and malignant progression. Notably, the ZDHHC17-MAP2K4-JNK/p38 signaling module contributes to GBM development and malignant progression by promoting GBM cell tumorigenicity and glioma stem cell (GSC) self-renewal. Moreover, we identify a small molecule, genistein, as a specific inhibitor to disrupt ZDHHC17-MAP2K4 complex formation for GBM cell proliferation and GSC self-renewal. Moreover, genistein, identified herein as a lead candidate for ZDHHC17-MAP2K4 inhibition, demonstrated potential therapeutic effect in patients with ZDHHC17-expressing GBM. Conclusions: Our study identified disruption of a previously unrecognized signaling module as a target strategy for GBM treatment, and provided direct evidence of the efficacy of its inhibition in glioma using a specific inhibitor.

Caspase recruitment domain-containing protein 9 (Card9) is a myeloid cell-specific signaling protein that plays a critical role in NF-κB and MAPK activation. This leads to initiation of the inflammatory cytokine cascade, and elicits the host immune response against microbial invasion, especially in fungal infection. Current research indicates that Card9 plays an important role in tumor progression. Here, we review the data from preclinical and clinical studies of Card9 and suggest the potential for Card9-targeted interventions in the prevention or treatment of certain tumors.

PURPOSE: All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the Gα(q) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gα(q) have shown promising preclinical results, but their therapeutic activity in distinct Gα(q) mutational contexts and in vivo have remained elusive. EXPERIMENTAL DESIGN: We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used in vitro and in vivo xenograft studies to assess the efficacy of Gα(q) inhibition as a single agent and in combination with MEK inhibition. RESULTS: We demonstrate that the Gα(q) inhibitor YM-254890 inhibited downstream signaling and in vitro growth in all mutants. In vivo, YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrate that the combination caused synergistic growth inhibition in vitro and tumor shrinkage in vivo. CONCLUSIONS: These data suggest that the combination of Gα(q) and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gα(q) in uveal melanoma.

Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT, and MEK/ERK signaling. However, the therapeutic efficacy of current JAK2 inhibitors is limited. We investigated the role of MEK/ERK signaling in MPN cell survival in the setting of JAK inhibition. Type I and II JAK2 inhibition suppressed MEK/ERK activation in MPN cell lines in vitro, but not in Jak2V617F and MPLW515L mouse models in vivo. JAK2 inhibition ex vivo inhibited MEK/ERK signaling, suggesting that cell-extrinsic factors maintain ERK activation in vivo. We identified PDGFRα as an activated kinase that remains activated upon JAK2 inhibition in vivo, and PDGF-AA/PDGF-BB production persisted in the setting of JAK inhibition. PDGF-BB maintained ERK activation in the presence of ruxolitinib, consistent with its function as a ligand-induced bypass for ERK activation. Combined JAK/MEK inhibition suppressed MEK/ERK activation in Jak2V617F and MPLW515L mice with increased efficacy and reversal of fibrosis to an extent not seen with JAK inhibitors. This demonstrates that compensatory ERK activation limits the efficacy of JAK2 inhibition and dual JAK/MEK inhibition provides an opportunity for improved therapeutic efficacy in MPNs and in other malignancies driven by aberrant JAK-STAT signaling.

Paradoxical oncogenesis was observed as early as one decade ago with pan-RAF inhibitors. The list of proliferative disorders has become even longer with the advent of selective BRAF inhibitors and includes not only skin premalignancies and malignancies, but also various epithelial, melanocytic, and vascular benign proliferations and, even now, non-skin malignancies. From the experimental side, the findings from an increasing number of important studies support a widely accepted mechanistic model of paradoxical oncogenesis. In the present review, we discuss the extent to which this model can be used to understand the variety of BRAF inhibitor-induced proliferative disorders. We also discuss a wider clinical and mechanistic definition of the paradoxical response to BRAF inhibitors, its links to the adaptive resistance to BRAF inhibition in melanoma, and its consequences for upcoming therapeutic developments.

Optimal activation of TLR pathways is crucial for the initiation of inflammatory responses and eliminating invading micro-organisms. However, excessive of TLR activation may lead to autoimmune and inflammatory diseases. Thus, TLR pathways should be tightly controlled. In this study, we identify Tob2, a Tob/BTG family member, as a suppressor of TLR pathways. Tob2 deficiency enhances TLR-induced NF-κB and MAPK activation and promotes the expression of proinflammatory cytokines in primary peritoneal macrophages of C57BL/6 mice. Furthermore, Tob2-defective C57BL/6 mice may be more susceptible to endotoxemic shock in vivo. Mechanistically, Tob2 interacts with TRAF6 and MyD88 and thus inhibits signaling from the MyD88–TRAF6 complex in primary peritoneal macrophages and HEK293T cells. Therefore, our results uncover a regulatory mechanism of TLR pathways and provide a potential target for the intervention of diseases with excessive TLR activation.

Sarcomas are deadly malignant tumors of mesenchymal origin occurring at all ages. The expression and function of the membrane-type matrix metalloproteinase MMP14 is closely related to the mesenchymal cell phenotype, and it is highly expressed in most sarcomas. MMP14 regulates the activity of multiple extracellular and plasma membrane proteins, influencing cell–cell and cell–extracellular matrix (ECM) communication. This regulation mediates processes such as ECM degradation and remodeling, cell invasion, and cancer metastasis. Thus, a comprehensive understanding of the biology of MMP14 in sarcomas will shed light on the mechanisms controlling the key processes in these diseases. Here, we provide an overview of the function and regulation of MMP14 and we discuss their relationship with clinical and pre-clinical MMP14 data in both adult and childhood sarcomas. Published version

Pilocytic astrocytomas (PA) are low-grade gliomas (pLGG) and are the most frequent childhood brain tumors. They are characterized by oncogene-induced senescence (OIS) initiated and sustained by senescence-associated secretory phenotype (SASP) factors. OIS and SASP in PA are thought to be driven by aberrations of the mitogen-activated protein kinase (MAPK) pathway (e.g. KIAA1549:BRAF fusion, BRAFV600E mutation, for the most common MAPK alterations occuring in PA), leading to its sustained activation. The MAPK pathway cascade is activated in a sequential manner: 1) ERK activation, which phosphorylates downstream partners in both cytoplasm and nucleus. 2) ERK-mediated induction of immediate early genes encoding transcription factors. 3) Induction of MAPK target genes expression. 4) Activation of downstream pathways. Our aim is to unravel the molecular partners involved at each level of the sustained MAPK pathway activation in pLGG with different genetic backgrounds (KIAA1549:BRAF fusion and BRAFV600E mutation), and leading to the induction of OIS and SASP factors expression. pLGG cell lines DKFZ-BT66 (KIAA1549:BRAF) and BT-40 (BRAFV600E) were treated with the MEK inhibitor trametinib at key time points, and gene expression profile analysis was performed, allowing transcriptome analysis at each step of the MAPK cascade. This will be combined with a whole proteomic and phospho-proteomic analysis. Combination of the transcriptome and proteome data layers will allow the identification of a) downstream targetable partners activated by the MAPK pathway involved in PA senescence, b) new putative targets that might bring benefit in combination with MAPK inhibitors.

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival of 9% and effective treatment options remain elusive. Oncogenic mutations of KRAS occur in >95% of PDACs and are well-established as the bona fide driver event. However, inhibition of KRAS oncoprotein or its downstream signaling cascades remains unsuccessful in PDAC patients. Furthermore, parallel survival pathways including constitutive activation of the NF-κB pathway poses an additional therapeutic barrier. Previous work from our lab showed that Interleukin-1 Receptor associated kinase 4 (IRAK4) is a major driver of NF-kB cascade in PDAC. Here, through an unbiased reverse phase protein array screen and RNA sequencing, we discovered IRAK4 controls MAPK activity downstream of KRAS. Ablation of IRAK4 completely abolishes RAS-induced transformation in human and murine cell lines. Mechanistically, we implicate a KRAS-driven IL-1β signaling loop that activates IRAK4 and uncover MAP3K8 (or TPL2/COT) as the kinase through which IRAK4 activates MEK and ERK. Suppression of TPL2 abrogates KRAS-driven MEK-ERK activity and transformed growth of PDAC cell lines. In addition, TPL2 inhibition suppresses p105/p50 NF-kB activation, a valuable phenomenon that distinguishes TPL2 inhibition from MEK inhibition. We find TPL2 inhibition synergizes with chemotherapy to suppress growth of PDAC cell lines in vitro and patient-derived xenograft tumor model in vivo. Analyses of PDAC tissue microarray showed TPL2 expression to be marginally associated with poor prognosis. Additionally, we are the first to characterize gain-of-function point mutations in TPL2 which hyperactivate MAPK and NF-kB, in part by preventing TPL2 protein degradation. Together, our study broadens the understanding of the oncogenic RAS signaling network and reveals IRAK4 and TPL2 as novel practical therapeutic targets in RAS-driven cancers. Citation Format: Paarth B. Dodhiawala, Namrata Khurana, Daoxiang Zhang, Yi Cheng, Lin Li, Kuljeet Seehra, Hongmei Jiang, Patrick M. Grierson, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Essential role of IRAK4/TPL2 signaling axis in MAPK activation by oncogenic RAS and genotoxic stress [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3039.

Introduction. Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer with increased metastatic potential. In the past, we have identified a gene expression profile that characterizes IBC, suggesting that a specific molecular biology underpins this devastating disease. Here, we explore the hypothesis that the molecular portrait of IBC is a reflection of underlying genomic alterations. Materials and Methods. Mutation and copy number variation (CNV) profiles for 663 genes were assembled from 2.352 publicly available primary tumor samples (subtype distribution: 1.520 HR+, 355 HER2+, 414 TNBC and 190 unassigned) including 127 profiles from patients with IBC. Gene-wise differences in the frequency of genomic aberrations between patients with and without IBC, stratified per subtype, were investigated using Chi-square testing with adjustment for multiple comparisons. Genomic perturbation differences of pathways and processes, represented by KEGG or Gene Ontology gene sets, were evaluated by collapsing mutation and CNV profiles across all genes associated with the respective gene sets. Finally, mutational signature (MS) profiles were calculated and compared between patients with and without IBC. Results. Seventy-six genes showed evidence of more extensive genomic alterations in samples from patients with IBC as compared to those without IBC (i.e. false discovery rate < 10%), whereas only 3 genes reveal the opposite pattern. Genes mutated in more than 15% (range 16.2% - 63,5%) of the IBC samples include: AXIN1, ERBB2, ERBB3, CBL, CTNNB1, CYP2D6, FGFR1, INSR, KIT, KMT2A, LRP1B, MYC, PBRM1, SACS, SMAD4, TP53 and ZNF217. Analysis of MS profiles revealed differences for signature 1 (i.e. age-related deamination of 5-methylcytosine), 2 (i.e. APOBEC3 activity), 3 (i.e. defective homologuous recombination), 11 (i.e. alkylating agents), 20 (i.e. DNA mismatch repair) and 24 (i.e. aflatoxin), of which MS 11 and 24 are more active in IBC. When evaluating the same panel of genes in TNBC only, 28 genes were retained, suggesting data are confounded by the subtype distribution. Pathway analysis revealed genomic perturbation of MAPK signaling and chromatin organizational processes in respectively 55% and 74% of TN IBCs. Discussion. These data suggest that IBC is characterized by an extensive mutational burden that results, amongst others in the activation of MAPK signaling as well as chromatin remodeling. The analysis of MS profiles does not provide a clear biological explanation for the increased frequency of genomic alterations in IBC, with APOBEC3 activity, defective homologous recombination, defective DNA mismatch repair and age-related deamination of 5-methylcytosinie all being more prominent in nIBC samples. Notably, the lower frequency of age-related C>T transitions is in line with younger age at diagnosis typical for patients with IBC. Citation Format: Van Laere S, Finetti P, Rypens C, Billet C, Birnbaum D, Vermeulen P, Viens P, Dirix L, Bertucci F. The mutational profile of inflammatory breast cancer reveals a higher mutational burden leading to MAPK activation and chromatin remodeling [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-04-04.

Although patients with melanoma generally benefit from BRAF or MEK targeted therapies, adverse events can occur on treatment, including the emergence of second malignancies. Evidence suggests unintended or paradoxical activation of MAPK signalling might underlie the majority of these second malignancies. The authors discuss the basis for this paradoxical MAPK activation, and the rationale for novel therapeutic strategies for the management of BRAF-inhibitor-induced neoplasia.

BRAF and MEK inhibitors, alone or in combination, are highly active in the 40% of patients with BRAF mutant metastatic melanoma. Despite this activity resistance often develops in patients treated with these agents. This review summarises the biology of the mitogen activated protein kinase (MAPK) pathway, with particular reference to the effects of BRAF and MEK inhibitors in BRAF mutant melanoma. The clinical and molecular predictors of response and mechanisms of resistance are discussed in detail along with the biological rationale and evidence for future treatment strategies in both MAPK inhibitor naive and resistant BRAF mutant melanoma.

INTRODUCTION: Osimertinib is a third-generation, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive EGFR-mutant lung cancer. The mutant-selective nature of osimertinib improves its tolerability by limiting its inhibition of wild-type EGFR compared to first- and second-generation EGFR inhibitors, making it a good candidate for rationally-designed combination therapies. One such combination, osimertinib plus the MEK inhibitor selumetinib (AZD6244; ARRY-142886), is currently being studied as part of the phase 1b TATTON trial (NCT02143466). Previous work by our group demonstrated that selumetinib may delay or reverse resistance to osimertinib in some cases; however, we anticipate that resistance to this combination will ultimately develop in patients. Here, we investigate acquired resistance to osimertinib and selumetinib combination therapy in vitro and in vivo. DESIGN: In cells sensitive to osimertinib plus selumetinib (hereafter referred to as combination-sensitive cells), ERK phosphorylation was monitored via Western blot over the course of a 7-day treatment with 200 nM osimertinib plus 1 µM selumetinib. To detect RAS-GTP, an active RAS precipitation was performed in combination-sensitive and combination-resistant cell lines following treatment with osimertinib. In combination-resistant cells, pharmacologic inhibitors of various MAPK pathway components were used to assess whether they could restore potency. Western blot analysis was used to confirm on-target effects. Lastly, an analysis of differences in gene expression between four isogenic sets of combination-sensitive and combination-resistant cell lines is currently ongoing. RESULTS: In cell lines that are sensitive to growth inhibition by the combination of osimertinib plus selumetinib, we observed complete re-activation of the MAPK pathway after 5 days of continuous exposure to both inhibitors. Additionally, RAS activity was elevated in combination-resistant cell lines, and these cells remained sensitive to the ERK inhibitor SCH772984. Likewise, the addition of a pan-RAF inhibitor restored the growth inhibitory effects of osimertinib plus selumetinib in combination-resistant cells, suggesting that incomplete inhibition of MAPK is responsible for resistance in these cells. Furthermore, an alternative MEK inhibitor, trametinib, was efficacious in combination with osimertinib in cell lines that were resistant to osimertinib plus selumetinib. CONCLUSION: These data identify a potential mechanism of resistance to a combination therapy that is currently being tested in the clinic. Specifically, these data demonstrate that re-activation of the MAPK pathway is a mechanism of resistance to osimertinib plus selumetinib and that this pathway is still targetable in combination-resistant cells. Citation Format: David Westover, Catherine B. Meador, Eiki Ichihara, Hayden F. Byrd, Cath Eberlein, Yingjun Yan, Darren A. Cross, Christine M. Lovly. Sustained MAPK activation as a mechanism of resistance to osimertinib plus selumetinib in models of EGFR-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3160. doi:10.1158/1538-7445.AM2017-3160

The word "through" is misspelled in the article title. The correct title is: A Novel SND1-BRAF Fusion Confers Resistance to c-Met Inhibitor PF-04217903 in GTL16 Cells through MAPK Activation. The correct citation is: Lee NV, Lira ME, Pavlicek A, Ye J, Buckman D, et al. (2012) A Novel SND1-BRAF Fusion Confers Resistance to c-Met Inhibitor PF-04217903 in GTL16 Cells through MAPK Activation. PLoS ONE 7(6): e39653. doi:10.1371/journal.pone.0039653

Alcohol consumption along with smoking is a well-known health hazard to human. How alcohol consumption potentiates the smoking mediated hazard is not clear. Previously we reported that DNA damage caused by tobacco smoke carcinogen (+/-) anti-benzo[a]pyrene-7, 8-diol-9,10-epoxide [BPDE] is responded by cells through induction of cell growth inhibition in different cell lines. Here we observed that ethanol (EtOH) treatment at physiologically relevant concentration (60mM) increases the DNA synthesis in DNA damaging carcinogen (BPDE) treated cells. BPDE treatment of cells elicits G1-S cell cycle arrest, but EtOH does not have any significant modulating effect of G1-S arrest, indicating increased DNA synthesis by EtOH is due to modulation of some other signaling event(s). We observed that EtOH co-treatment/ pretreatment potentiates BPDE induced phosphorylation and activation of extracellular regulated kinase 1/2 (ERK1/2). Interestingly, treatment of cells with MEK1 inhibitor (PD09059) significantly reduced EtOH's ability to increase DNA synthesis in BPDE treated cells. All together, these findings suggest that the ability of EtOH to potentiate BPDE-induced ERK activation may potentiates PAH-induced tumorigenesis. [Supported by NIH grant # R03 ES021779]. Citation Format: Manoj K. Pandey, Jagat J. Mukherjee, Dhimant H. Desai, Shantu G. Amin, Subodh Kumar. Ethanol potentiates tobacco smoke carcinogens-induced MAPK activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2734. doi:10.1158/1538-7445.AM2015-2734

ISEE 22nd Annual Conference, Seoul, Korea, 28 August-1 September 2010: Heavy Metals and Metalloids

9578 Background: Fewer than 20% of patients (pts) with pancreatic cancer survive 5 years following pancreatico-duodenectomy. Limited data exist regarding downstream activation of EGFR signaling in ...