Identification of head and neck cancers (SCCHN) that may respond to dual inhibition of EGFR and HER3 signaling.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5575-5575
Author(s):  
David S. Shames ◽  
Howard Stern ◽  
Kim Walter ◽  
Brittany Jiang ◽  
Ling Fu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Bimodal Distribution ◽  
Autocrine Signaling ◽  
Oncogenic Signaling ◽  
Epithelial Cancers ◽  
Formalin Fixed Paraffin Embedded ◽  
Dual Action ◽  
High Level

5575 Background: Oncogenic signaling through the epidermal growth factor receptor family is one of the most frequent alterations found in human epithelial cancers. These receptor tyrosine kinases mediate their effects via high-level co-expression and homo- and heterodimerization events that drive tumor growth, metastasis, and survival. Extensive preclinical studies suggested that some cell lines depend on oncogenic autocrine signaling through HER3 (Wilson et al.). This phenotype was particularly prominent in cell lines derived from SCCHN and was strongly correlated with high HRG expression. Interestingly, two patients with SCCHN tumors that expressed high levels of HRG in our phase Ia trial (abstract #95245) of MEHD7954A, a dual-action human IgG1 antibody that blocks ligand binding to EGFR and HER3 (Schaefer et al.) had partial responses. To further explore the hypothesis that high-level HRG expression defines a sub-population of SCCHN that may be sensitive to agents targeting HER3, and to identify other potential target indications for the development of MEHD7954A, we evaluated the expression of HRG in large cohorts of multiple solid tumor indications. Methods: HER3 and HRG expression was analyzed by qRT-PCR in 648 formalin-fixed paraffin embedded primary tumor samples from patients with NSCLC, SCCHN, melanoma, CRC and triple-negative breast cancer. Results: SCCHN-derived tumor samples had the highest levels of HRG expression, exhibiting a bimodal distribution in SCCHN – a pattern that is clearly distinct when compared to other tumor types. These data suggest that high HRG levels and potentially HER3-dependent autocrine signaling occur more frequently in SCCHN than in other tumors. Further we investigated whether overexpression of HRG in SCCHN correlated with stage and disease outcome. Updated results from these extended studies will be presented. Conclusions: SCCHN tumors exhibit bimodal expression of HRG, suggesting that HRG expression levels may be useful in identifying a subset of patients most likely to benefit from inhibition of HER3 activity. Antitumor activity in such patients has been observed in a phase I study of MEHD7954A (abstract #95245).

Endocrine Resistance: What Do We Know?

2013 ◽  
pp. e37-e42 ◽  
Author(s):  
Todd W. Miller
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
De Novo ◽  
Early Stage ◽  
Effective Means ◽  
Endocrine Resistance ◽  
Large Body ◽  
Growth Factor Receptor ◽  
Oncogenic Signaling

Adjuvant therapy with antiestrogens targeting estrogen receptor α (ER) signaling prevents disease recurrence in many patients with early-stage ER+ breast cancer. However, a significant number of cases exhibit de novo or acquired endocrine resistance. While other clinical subtypes of breast cancer (HER2+, triple-negative) have disproportionately higher rates of mortality, ER+ breast cancer is responsible for at least as many deaths because it is the most common subtype. Therefore, identifying mechanisms that drive endocrine resistance is a high clinical priority. A large body of experimental evidence indicates that oncogenic signaling pathways underlie endocrine resistance, including growth factor receptor tyrosine kinases (HER2, epidermal growth factor receptor [EGFR], fibroblast growth factor receptor 1/2 [FGFR], insulin-like growth factor-1 receptor [IGF-1R]/ insulin receptor [InsR]), PI3K/AKT/ mTOR, MAPK/ERK, Src, CDK4/CDK6, and ER itself. Combined targeting of ER and such pathways may be the most effective means to combat antiestrogen resistance, and clinical trials testing such strategies show promising results. Herein, we discuss pathways associated with endocrine resistance, biomarkers that may be useful to predict response to targeted agents, and avenues for further exploration to identify strategies for the treatment of patients with endocrine-resistant disease.

scholarly journals Transcriptome of Two Canine Prostate Cancer Cells Treated With Toceranib Phosphate Reveals Distinct Antitumor Profiles Associated With the PDGFR Pathway

2020 ◽  
Vol 7 ◽  
Author(s):  
Priscila E. Kobayashi ◽  
Patrícia F. Lainetti ◽  
Antonio F. Leis-Filho ◽  
Flávia K. Delella ◽  
Marcio Carvalho ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Protein Expression ◽  
Cell Line ◽  
Cell Lines ◽  
Protein Interactions ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Upregulated Genes

Canine prostate cancer (PC) presents a poor antitumor response, usually late diagnosis and prognosis. Toceranib phosphate (TP) is a nonspecific inhibitor of receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-KIT. This study aimed to evaluate VEGFR2, PDGFR-β, and c-KIT protein expression in two established canine PC cell lines (PC1 and PC2) and the transcriptome profile of the cells after treatment with TP. Immunofluorescence (IF) analysis revealed VEGFR2 and PDGFR-β protein expression and the absence of c-KIT protein expression in both cell lines. After TP treatment, only the viability of PC1 cells decreased in a dose-dependent manner. Transcriptome and enrichment analyses of treated PC1 cells revealed 181 upregulated genes, which were related to decreased angiogenesis and cell proliferation. In addition, we found upregulated PDGFR-A, PDGFR-β, and PDGF-D expression in PC1 cells, and the upregulation of PDGFR-β was also observed in treated PC1 cells by qPCR. PC2 cells had fewer protein-protein interactions (PPIs), with 18 upregulated and 22 downregulated genes; the upregulated genes were involved in the regulation of parallel pathways and mechanisms related to proliferation, which could be associated with the resistance observed after treatment. The canine PC1 cell line but not the PC2 cell line showed decreased viability after treatment with TP, although both cell lines expressed PDGFR and VEGFR receptors. Further studies could explain the mechanism of resistance in PC2 cells and provide a basis for personalized treatment for dogs with PC.

scholarly journals SORLA-driven endosomal trafficking regulates the oncogenic fitness of HER2

2018 ◽  
Author(s):  
Mika Pietilä ◽  
Pranshu Sahgal ◽  
Emilia Peuhu ◽  
Niklas Jäntti ◽  
Ilkka Paatero ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Endosomal Trafficking ◽  
Oncogenic Signaling ◽  
Membrane Expression ◽  
Cationic Amphiphilic Drugs ◽  
Amphiphilic Drugs

AbstractHuman epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. Endosomal trafficking of many other receptor tyrosine kinases regulates their oncogenic signaling, but the prevailing view is that HER2 is retained on the cell surface. Here we reveal that in cancer cells Sortilin related receptor 1 (SORLA; SORL1) forms a complex with HER2 and regulates its subcellular distribution by promoting recycling of endosomal HER2 back to plasma membrane. Expression of SORLA in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA targets HER2 to late endosomal/lysosomal compartments, impairs HER2-driven signaling and in vivo tumor growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

scholarly journals A Bispecific Inhibitor of the EGFR/ADAM17 Axis Decreases Cell Proliferation and Migration of EGFR-Dependent Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 411
Author(s):  
Abel Soto-Gamez ◽  
Deng Chen ◽  
Anke G.E. Nabuurs ◽  
Wim J Quax ◽  
Marco Demaria ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Fusion Protein ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Mutant Cell ◽  
Growth Factor Receptor ◽  
Autocrine Signaling ◽  
Inhibition Of Proliferation ◽  
Innovative Strategy ◽  
Egfr Ligands

Dysregulated epidermal growth factor receptor (EGFR) is an oncogenic driver of many human cancers, promoting aberrant cell proliferation, migration, and survival. Pharmacological targeting of EGFR is often challenged by acquired mechanisms of resistance. Ligand-dependent mechanisms in EGFR wild-type cells rely on ligand or receptor overexpression, allowing cells to outcompete inhibitors and perpetuate signaling in an autocrine manner. Importantly, EGFR ligands are synthesized as membrane-bound precursors that must be solubilized to enable receptor-ligand interactions. The A disintegrin and metalloproteinase 17 (ADAM17) is considered the main sheddase of several EGFR ligands, and a potential pharmacological target. However, its broad substrate range and ubiquitous expression complicate its therapeutic targeting. Here, we present a novel bispecific fusion protein construct consisting of the inhibitory prodomain of ADAM17 (TPD), fused to an EGFR-targeting designed ankyrin repeat protein (DARPin). TPD is a natural inhibitor of ADAM17, maintaining the protease in a zymogen-like form. Meanwhile, the high affinity anti-EGFR DARPin E01 binds to EGFR and inhibits ligand binding. The resulting fusion protein E01-GS-TPD retained binding ability to both molecular targets EGFR and ADAM17. The large difference in affinity for each target resulted in enrichment of the fusion protein in EGFR-positive cells compared to EGFR-negative cells, suggesting a possible application in autocrine signaling inhibition. Accordingly, E01-GS-TPD decreased migration and proliferation of EGFR-dependent cell lines with no significant increase in apoptotic cell death. Finally, inhibition of proliferation was observed through EGFR ligand-dependent mechanisms as growth inhibition was not observed in EGFR mutant or KRAS mutant cell lines. The use of bispecific proteins targeting the EGFR/ADAM17 axis could be an innovative strategy for the treatment of EGFR-dependent cancers.

scholarly journals Lactate Engages Receptor Tyrosine Kinases Axl, Tie2, and Vascular Endothelial Growth Factor Receptor 2 to Activate Phosphoinositide 3-Kinase/Akt and Promote Angiogenesis

2013 ◽  
Vol 288 (29) ◽  
pp. 21161-21172 ◽  
Author(s):  
Guo-Xiang Ruan ◽  
Andrius Kazlauskas
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Akt Pathway ◽  
Vegf Receptor ◽  
Vascular Perfusion ◽  
Phosphoinositide 3 Kinase ◽  
High Level ◽  
Aortic Explants

Although a high level of lactate is quintessential to both tumors and wound healing, the manner by which lactate impacts endothelial cells to promote angiogenesis and thereby create or restore vascular perfusion to growing tissues has not been fully elucidated. Here we report that lactate activated the PI3K/Akt pathway in primary human endothelial cells. Furthermore, activating this signaling pathway was required for lactate-stimulated organization of endothelial cells into tubes and for sprouting of vessels from mouse aortic explants. Lactate engaged the PI3K/Akt pathway via ligand-mediated activation of the three receptor tyrosine kinases Axl, Tie2, and VEGF receptor 2. Neutralizing the ligands for these receptor tyrosine kinases, pharmacologically inhibiting their kinase activity or suppressing their expression largely eliminated the ability of cells and explants to respond to lactate. Elucidating the mechanism by which lactate communicates with endothelial cells presents a previously unappreciated opportunity to improve our understanding of the angiogenic program and to govern it.

Phosphotyrosine-Based Phosphoproteomics of a Panel AML Cell Lines Reveals Oncogenic Signaling and Hyperactive Tyrosine Kinases as Targets for Treatment

2017 ◽  
Vol 17 (10) ◽  
pp. S2-S3
Author(s):  
Carolien van Alphen ◽  
Jacqueline Cloos ◽  
Sander R. Piersma ◽  
Jaco C. Knol ◽  
Thang V. Pham ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tyrosine Kinases ◽  
Oncogenic Signaling

scholarly journals Dual targeting of FGFR3 and the ERBB receptor family or AXL enhances the efficacy of FGFR inhibitors in FGFR3 fusion-driven bladder cancer

2021 ◽  
Author(s):  
David Lau ◽  
Margeaux Hodgson-Garms ◽  
Austen Lavis ◽  
Ian Luk ◽  
Laura Jenkins ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Viability ◽  
Cell Lines ◽  
Combination Treatment ◽  
Tyrosine Kinases ◽  
Cell Signalling ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Concomitant Increase ◽  
Erbb Family

Abstract BackgroundMutations and fusions in Fibroblast Growth Factor Receptor 3 (FGFR3) occur in 10-20% of metastatic urothelial carcinomas, and can confer sensitivity to FGFR inhibitors such as BGJ398 and erdafitinib. However, responses to these agents are often short-lived due to the development of acquired resistance. The objective of this study was to identify mechanisms of acquired resistance to FGFR inhibitors in two previously uncharacterized bladder cancer cell lines harbouring FGFR3 fusions, and assess rational combination therapies to enhance their activity. MethodsAcquired resistance to FGFR inhibitors was generated in two FGFR3 fusion harbouring cell lines, SW780 (FGFR3-BAIAP2L1 fusion) and RT4 (FGFR3-TACC3 fusion), by either long-term exposure to increasing concentrations of BGJ398 or sustained exposure to high concentrations of drug. Alterations in levels of key cell signalling regulators was assessed in resistant lines by phospho-RTK arrays and immunoblotting. Synergy between BGJ398 and alternate targeted therapies was explored using cell viability and apoptosis assays.ResultsAcquired resistance to BGJ398 in SW780 and RT4 cells was associated with increased expression of members of ERBB family of receptor tyrosine kinases and pAXL. Combination treatment of resistant cells with an FGFR inhibitor and either a pan-ERBB or an AXL inhibitor overcame this resistance. We also noted rapid reactivation of pERK in parental FGFR3 fusion-driven lines within 4-72 hours of BGJ398 treatment, with concomitant increase in pERBB3. Up-front combination treatment with BGJ398 and the pan-ERBB inhibitor AZD8931 delayed the reactivation of pERK, and induced a synergistic inhibition of cell viability and a concomitant increase in apoptosis.ConclusionsWe identify increased activation of AXL and ERBB family receptors as mechanisms of resistance to FGFR inhibition. Our findings suggest that upfront combination treatment with FGFR and pan-ERBB inhibitors warrants further investigation for FGFR3-fusion harbouring bladder cancers.

Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 4051-4059 ◽  
Author(s):  
Christoph Renné ◽  
Klaus Willenbrock ◽  
Ralf Küppers ◽  
Martin-Leo Hansmann ◽  
Andreas Bräuninger
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Activating Mutations ◽  
Rtk Signaling ◽  
Non Hodgkin Lymphoma ◽  
Classic Hodgkin Lymphoma ◽  
Autocrine Loops

AbstractThe pathogenesis of Hodgkin lymphoma (HL) is still largely unknown. Based on a search for footprints of pathogenetic mechanisms in global RNA expression data of Hodgkin/Reed-Sternberg (HRS) cell lines, we analyzed the expression and activation of 6 receptor tyrosine kinases (RTKs) in classic HL. Immunohistochemistry revealed that the RTKs platelet-derived growth factor receptor A (PDGFRA), DDR2, EPHB1, RON, TRKB, and TRKA were each expressed in HRS cells in 30% to 75% of patients. These RTKs were not expressed in normal B cells, the origin of HRS cells, or in most B-cell non-Hodgkin lymphoma (NHL). In the majority of patients at least one RTK was expressed, and in most patients several RTKs were coexpressed, most prominently in Hodgkin lymphoma of the nodular sclerosis subtype. Phosphotyrosine-specific antibodies revealed exemplarily the activation of PDGFRA and TRKA/B and an elevation of cellular phosphotyrosine content. Immunohistochemistry for RTK ligands indicated that DDR2 and TRKA are likely activated in a paracrine fashion, whereas PDGFRA and EPHB1 seem to be activated by autocrine loops. Activating mutations were not detected in cDNA encoding the RTKs in HRS cell lines. These findings show the unprecedented coexpression of multiple RTKs in a tumor and indicate that aberrant RTK signaling is an important factor in HL pathogenesis and that it may be a novel therapeutic target.

Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Triple Negative ◽  
Growth Factor Receptor ◽  
Engineered Nanoparticles ◽  
Efficacy Evaluation ◽  
Dual Action ◽  
Epidermal Growth ◽  
Laminin 411 ◽  
Immunologic Analysis

Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safetyfor cancer patient's treatment. All-in-one covalent nanodrugs of the third generation have beensynthesized based on a poly(β-L-malic acid) (PMLA) platform, targeting human triple-negativebreast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blockingsynthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumorvascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicityat low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and singleactionprecursor nanoconjugates were assessed under in vitro conditions and in vivo with multipletreatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo withdifferent drugs included blood hematologic and immunologic analysis after multiple intravenousadministrations. The present study demonstrates that the dual-action nanoconju-gate is highlyeffective in preclinical TNBC treatment without side effects, supported by hematologic andimmunologic assays data. PMLA-based nanodrugs of the Polycefin™ family passed multipletoxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimizedand efficacious for the treatment of cancer patients in the future.

Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors

2020 ◽  
Vol 20 (18) ◽  
pp. 1628-1639
Author(s):  
Sergi Gómez-Ganau ◽  
Josefa Castillo ◽  
Andrés Cervantes ◽  
Jesus Vicente de Julián-Ortiz ◽  
Rafael Gozalbes
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Binding Affinity ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Significant Activity ◽  
Epidermal Growth

Background: The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma. Methods: We have followed a structure-based virtual screening (SBVS) procedure with a library composed of several commercial collections of chemicals (615,462 compounds in total) and the 3D structure of EGFR obtained from the Protein Data Bank (PDB code: 1M17). The docking results from this campaign were then ranked according to the theoretical binding affinity of these molecules to EGFR, and compared with the binding affinity of erlotinib, a well-known EGFR inhibitor. A total of 23 top-rated commercial compounds displaying potential binding affinities similar or even better than erlotinib were selected for experimental evaluation. In vitro assays in different cell lines were performed. A preliminary test was carried out with a simple and standard quick cell proliferation assay kit, and six compounds showed significant activity when compared to positive control. Then, viability and cell proliferation of these compounds were further tested using a protocol based on propidium iodide (PI) and flow cytometry in HCT116, Caco-2 and H358 cell lines. Results: The whole six compounds displayed good effects when compared with erlotinib at 30 μM. When reducing the concentration to 10μM, the activity of the 6 compounds depends on the cell line used: the six compounds showed inhibitory activity with HCT116, two compounds showed inhibition with Caco-2, and three compounds showed inhibitory effects with H358. At 2 μM, one compound showed inhibiting effects close to those from erlotinib. Conclusion: Therefore, these compounds could be considered as potential primary hits, acting as promising starting points to expand the therapeutic options against a wide range of cancers.

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