Mechanisms of resistance to Erbitux (anti–epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells

Arnoletti, J. Pablo; Buchsbaum, Donald J.; Huang, Zhiqiang; Hawkins, Ashley E.; Khazaeli, M. B.; Kraus, Matthias H.; Vickers, Selwyn M.

doi:10.1016/j.gassur.2004.09.021

Cited by 41 publications

(31 citation statements)

References 28 publications

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“…This is consistent with observations that MDCK cells require activation of Src, such as through expression of v-Src or after growth factor stimulation, to disassemble cell borders before separation (Palacios et al, 2001(Palacios et al, , 2005Orlichenko et al, 2006), whereas PANC-1 and BxPC-3 cells exhibit weak junctions, form modest monolayers, and have elevated signaling cascades as part of the neoplastic condition (L.O., S.G.W., and M.A.M. unpublished observations; Korc et al, 1986;Arnoletti et al, 2004;Ali et al, 2005). Thus, these cells may exhibit a more dynamic turnover of E-cad, contributing to a more constitutive formation of Cav1-coated, E-cad-containing endosomes as well as the malignant phenotype.…”

Section: Egf-induced Internalization Of Adherens Junction Proteins Insupporting

confidence: 88%

“…This observation is consistent with the fact that these cells have amplified EGF receptor signaling (L.O., S.G.W., and M.A.M. unpublished observations; Arnoletti et al, 2004;Ali et al, 2005), modest cell-cell borders, and spontaneously form Cav1-coated endosomes in the absence of EGF treatment (Supplemental Figure S1, b and bЈ). Finally, to test for an association between Cav1 and E-cad and whether this putative interaction might be increased upon EGF stimulation, Cav1 was immunoprecipitated from MDCK and BxPC-3 cells at various time points after EGF stimulation.…”

Section: Egf-induced Caveolae Formation Leads To An Increased Associasupporting

confidence: 86%

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Caveolae Mediate Growth Factor-induced Disassembly of Adherens Junctions to Support Tumor Cell Dissociation

Orlichenko

Weller

Cao

et al. 2009

MBoC

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Remodeling of cell-cell contacts through the internalization of adherens junction proteins is an important event during both normal development and the process of tumor cell metastasis. Here we show that the integrity of tumor cell-cell contacts is disrupted after epidermal growth factor (EGF) stimulation through caveolae-mediated endocytosis of the adherens junction protein E-cadherin. Caveolin-1 and E-cadherin closely associated at cell borders and in internalized structures upon stimulation with EGF. Furthermore, preventing caveolae assembly through reduction of caveolin-1 protein or expression of a caveolin-1 tyrosine phospho-mutant resulted in the accumulation of E-cadherin at cell borders and the formation of tightly adherent cells. Most striking was the fact that exogenous expression of caveolin-1 in tumor cells that contain tight, well-defined, borders resulted in a dramatic dispersal of these cells. Together, these findings provide new insights into how cells might disassemble cell-cell contacts to help mediate the remodeling of adherens junctions, and tumor cell metastasis and invasion. INTRODUCTIONPolarized epithelial cells such as those in ductular organs, including the pancreas, form and maintain their tubular tissue architecture through regulated associations with adjacent cells (Hogan and Kolodziej, 2002;Lubarsky and Krasnow, 2003;Zegers et al., 2003). The integrity of these lateral interactions is mediated, in part, by adherens junctions (AJs), of which the transmembrane protein E-cadherin (E-cad) is a major component. On the extracellular side, homophilic antiparallel interactions between E-cad molecules present on adjacent cells mediate the assembly and maintenance of AJs, whereas on the intracellular side the cytoplasmic tail of E-cad is associated with an array of actin cytoskeletal proteins as well as signaling molecules such as catenins, small GTPases, and nonreceptor tyrosine kinases (Perez-Moreno et al., 2003;Gumbiner, 2005). Although maintenance of stable junctions is important for tissue integrity and the functional properties of polarized epithelia, AJs are also dynamic structures undergoing cycles of assembly and disassembly. Indeed, reorganization of AJs is a key aspect of tissue morphogenesis both during normal development as well as tumor cell metastasis, when the structural integrity of AJs is compromised as tumor cells lose polarity and subsequently dissociate before migration (Thiery, 2002;Cavallaro and Christofori, 2004).Pancreatic cancer is a particularly deadly disease and is listed as one of the top five most lethal cancers in the United States (Jemal et al., 2006). Although less prevalent than other cancers, its mortality rate is well over 90% within 6 mo of diagnosis. This exceptionally high lethality is due to a lack of early diagnostic tools, the dispersed organization of the pancreas within the abdomen, and a significant propensity of neoplastic cells to disseminate and migrate from the pancreas to nearby organs (Shi et al., 2001;Freelove and Walling, 2006).A reduction ...

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Section: Egf-induced Internalization Of Adherens Junction Proteins Insupporting

confidence: 88%

Section: Egf-induced Caveolae Formation Leads To An Increased Associasupporting

confidence: 86%

Caveolae Mediate Growth Factor-induced Disassembly of Adherens Junctions to Support Tumor Cell Dissociation

Orlichenko

Weller

Cao

et al. 2009

MBoC

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“…The antitumour effect of cetuximab has been assessed in different preclinical models of human pancreatic adenocarcinoma, both as a single agent and in combination with gemcitabine [13,14,15,16,17]. Using the human pancreatic cancer cell line L3.6p1 and the orthotopic tumour model, it has been shown that cetuximab effectively blocks ErbB-1 autophosphorylation in vitro and in vivo [14].…”

Section: Tyrosine Kinases As Therapeutic Targets For Pancreatic Cancementioning

confidence: 99%

“…The in vivo effect was further enhanced when gemcitabine was added in mice with subcutaneously implanted BxPC-3 pancreatic tumour xenografts [16]. Using the combination of cetuximab, gemcitabine and radiation as treatment for different pancreatic cancer cell lines, Buchsbaum et al [13,15] could induce the highest levels of apoptosis in vitro and complete regression of established MiaPaCa-2 tumours in vivo. However, partial resistance to this combination therapy was found in BxPC-3 pancreatic tumours, which was possibly caused by variable downstream signalling [13,18].…”

Section: Tyrosine Kinases As Therapeutic Targets For Pancreatic Cancementioning

confidence: 99%

A Review of Kinases Implicated in Pancreatic Cancer

2009

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“…Among anti-EGFR monoclonal antibodies, cetuximab (Erbitux ® ) is a chimeric mAb which targets the extracellular domain, blocks ligand binding and thus prevents EGFR activation. Cetuximab inhibits cell proliferation primarily by cell cycle control (8,9) but also modifications of EGFR internalization and degradation (10). Cetuximab is approved in combination with chemotherapy or ionizing radiations in the treatment of metastatic colorectal cancer (mCRC) and HNSCC (11,12).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms underlying resistance to cetuximab in the HNSCC cell line: Role of AKT inhibition in bypassing this resistance

Lansiaux¹

2010

Int J Oncol

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Abstract. EGFR is frequently overexpressed in head and neck squamous cell cancer (HNSCC). Cetuximab is a monoclonal antibody designed to interact with EGFR, block its activation, reduce the downstream signaling pathways and induce EGFR internalization. This study aims to investigate the role of the EGFR signaling pathway and EGFR internalization in a cetuximab-resistant cell line and to propose a new therapeutic strategy to optimize treatment of HNSCC. The HNSCC cell line, CAL33 was sensitive to gefitinib but resistant to cetuximab. Cetuximab induces an unexpected EGFR phosphorylation in CAL33 cells similarly to EGF but this EGFR activation does not trigger EGFR internalization/degradation, the process currently implicated in the response to cetuximab. Cetuximab inhibits ERK and AKT phosphorylation in cetuximab-sensitive A431 cells, whereas the level of AKT phosphorylation is unmodified in cetuximab-resistant cells. Interestingly, CAL33 cells harbor a PIK3CA mutation. The treatment of CAL33 cells with PI3K inhibitor and cetuximab restores the inhibition of AKT phosphorylation and induces growth inhibition. Our results indicate that EGFR internalization is impaired by cetuximab treatment in CAL33 cells and that the AKT pathway is a central element in cetuximab resistance. The combination of cetuximab with a PI3K inhibitor could be a good therapeutic option in PIK3CA-mutated HNSCC.

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Mechanisms of resistance to Erbitux (anti–epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells

Cited by 41 publications

References 28 publications

Caveolae Mediate Growth Factor-induced Disassembly of Adherens Junctions to Support Tumor Cell Dissociation

Caveolae Mediate Growth Factor-induced Disassembly of Adherens Junctions to Support Tumor Cell Dissociation

A Review of Kinases Implicated in Pancreatic Cancer

Mechanisms underlying resistance to cetuximab in the HNSCC cell line: Role of AKT inhibition in bypassing this resistance

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