Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer

Jimeno, Antonio; Rubio-Viqueira, Belén; Amador, María L.; Grunwald, Victor; Maitra, Anirban; Iacobuzio‐Donahue, Christine A.; Hidalgo, Manuel

doi:10.1158/1535-7163.mct-06-0448

Cited by 27 publications

(23 citation statements)

References 42 publications

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“…Moreover, the results of this study showed that rare and potentially "druggable" oncogenic mutations may exist in many common tumor types regarded as WT against well-known oncogenes (20). Thus, there is a clear need for more rational therapeutic strategies of genetically complex tumor cells, and several studies have already provided initial rational combination therapies (22)(23)(24). In this study, we characterize AZD6244 (ARRY-142886), a novel MAP/ERK kinase (MEK) inhibitor that exerts antiproliferative effects on human gastric cancer cell lines that are resistant to gefitinib.…”

Section: Introductionmentioning

confidence: 85%

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Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells

Yoon

Kim

Han

et al. 2009

Molecular Cancer Therapeutics

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EGFR tyrosine kinase inhibitors have shown promising efficacy in the treatment of tumors with EGFR mutations and amplifications. However, tyrosine kinase inhibitors have also proven ineffective against most tumors with EGFR wild-type (WT) alleles. Although some genetic changes, including the KRAS mutation, have been shown to confer resistance to tyrosine kinase inhibitors, novel strategies for the treatment of cancer patients with tumors harboring EGFR WT alleles have yet to be thoroughly delineated. The principal objective of this study was to improve our current understanding of drug interactions between EGFR and MAP/ERK kinase (MEK) inhibitors in an effort to gain insight into a novel therapeutic strategy against EGFR WT tumors. Using a panel of human EGFR WT gastric cancer cell lines, we showed that gastric cancer cells harboring the KRAS mutation were selectively sensitive to MEK inhibition as compared with those cells harboring KRAS and PI3K mutations and KRAS WT alleles. However, all cell lines were found to be resistant to EGFR inhibition. The results from Western blots and phosphoprotein arrays showed that, in MEK inhibitor resistant cell lines, AKT was activated through the EGFR/HER3/PI3K pathway following AZD6244 (ARRY-142886) treatment. Blockade of this feedback mechanism through the targeting of MEK and EGFR resulted in detectable synergistic effects in some cell lines in vitro and in vivo. Our results provide the basis for a rational combination strategy against human EGFR WT gastric cancers, predicated on the understanding of cross-talk between the MEK and EGFR pathways. [Mol Cancer Ther 2009;8(9):2526-36]

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Section: Introductionmentioning

confidence: 85%

“…EGFR (exons [18][19][20][21][22][23][24], KRAS (exons 1-3), and BRAF (exon 15) were then sequenced using the previously described primers and methods (10,25,26). All sequencing reactions were conducted in the forward and reverse directions.…”

Section: Methodsmentioning

confidence: 99%

Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells

Yoon

Kim

Han

et al. 2009

Molecular Cancer Therapeutics

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“…S1). 5 However, a dose of 1 Amol/L was selected for in vitro experiments to reduce direct cytotoxic effects. In Western blot analysis, stimulation of endothelial cells with VEGF-A led to an activation of Erk and SAPK signaling intermediates and NVP-AAL881 markedly reduced phosphorylation of these intermediates (Fig.…”

Section: Effects Of Raf/vegfr2 Inhibition On Endothelial Cells and Pementioning

confidence: 99%

“…In pancreatic cancer, RasRaf-MAPK signaling is required for mediating growth factor-induced (such as epidermal growth factor) oncogenic effects and activation of this pathway is associated with tumor progression (proliferation) and invasiveness (cell migration; refs. 4,5). Moreover, it was shown that dual MAPK/epidermal growth factor receptor inhibition significantly decreases growth of KRAS-mutated pancreatic cancer tumors in preclinical models, whereas solely blocking epidermal growth factor receptor (erlotinib) has no growth-inhibitory effect, suggesting that targeting the RasRaf-MAPK pathway is superior to anti-epidermal growth factor receptor therapy in KRAS-mutated pancreatic cancer (5).…”

Section: Introductionmentioning

confidence: 99%

“…4,5). Moreover, it was shown that dual MAPK/epidermal growth factor receptor inhibition significantly decreases growth of KRAS-mutated pancreatic cancer tumors in preclinical models, whereas solely blocking epidermal growth factor receptor (erlotinib) has no growth-inhibitory effect, suggesting that targeting the RasRaf-MAPK pathway is superior to anti-epidermal growth factor receptor therapy in KRAS-mutated pancreatic cancer (5). However, activating V600 B-Raf mutations are less frequently observed in this cancer entity (6).…”

Section: Introductionmentioning

confidence: 99%

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Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Lang¹,

Schachtschneider²,

Moser³

et al. 2008

Molecular Cancer Therapeutics

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The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growthinhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer.

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Development of molecularly targeted therapies in biliary tract cancers: Reassessing the challenges and opportunities

Hezel

2011

Hepatology

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Biliary tract cancers (BTCs), which encompass intra-and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are a genetically diverse collection of cancers. Most patients with BTC will present with unresectable or metastatic disease. Although the standard systemic chemotherapy approaches are emerging, the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. Recent early-stage clinical trials with targeted therapies appear promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here we summarize the relevant molecular pathogenesis, recent and ongoing clinical trials with targeted agents, and the key issues in clinical trial design in BTC. (HEPATOLOGY 2011;53:695-704)

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Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer

Cited by 27 publications

References 42 publications

Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells

Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Development of molecularly targeted therapies in biliary tract cancers: Reassessing the challenges and opportunities

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