ErbB receptors: possible therapeutic targets in prostate cancer?

Ratan, Hari L.; Gescher, Andreas; Steward, W.P.; Mellon, J. Kilian

doi:10.1111/j.1464-410x.2003.04503.x

Cited by 30 publications

(23 citation statements)

References 31 publications

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“…Epigenetic changes leading to the overexpression of the erbB1 and erbB2/neu receptors are also involved in tumor progression 9 and in disease relapse and progression to androgen independence in human PCa. 10,11 Studies from many groups have demonstrated critical roles for a series of peptide growth factors and corresponding epithelium-expressed receptor tyrosine kinases (RTKs) in the normal prostate and/or in PCa. There are multiple lines of evidence indicating that deregulation of the EGFR signal transduction pathway plays a critical role in the processes of tumor pathogenesis, growth and metastasis.…”

mentioning

confidence: 99%

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Festuccia

Gravina

Angelucci

et al. 2005

Intl Journal of Cancer

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Progression from an androgen-dependent to an androgen-independent state often occurs in patients with prostate cancer (PCa) who undergo hormonal therapy. We have investigated whether inhibition of the epidermal growth factor receptor (EGFR) signaling pathway affects the antitumor effect of a nonsteroidal antiandrogen. Gefitinib (Iressa), an EGFR tyrosine kinase inhibitor, and bicalutamide (Casodex), a nonsteroidal antiandrogen [androgen receptor (AR) antagonist], were administered alone and in combination to AR-positive human PCa cell lines. FACS analysis showed lower EGFR expression levels on AR-positive cells (LNCaP, CWR22, CWR22R 2152 and AR-transfected DU145 cell lines) compared with AR-negative cells (DU145, PC3 and TSUPr1). Moreover, in AR-transfected DU145 cells, chronic treatment with bicalutamide increased EGFR expression to levels similar to androgen-independent DU145 cells. All AR-positive PCa cell lines were sensitive to gefitinib (IC 50 = 0.1-0.6 mM), whereas higher concentrations of bicalutamide were needed to reduce AR-positive PCa cell line proliferation (IC 50 = 0.8-2.0 mM). Low doses of gefitinib increased the antitumor effects of bicalutamide by strongly reducing the IC 50 of bicalutamide (approximately 10-fold). Similarly, bicalutamide increased the antiproliferative effects of gefitinib by reducing the IC 50 of gefitinib (approximately 5-fold). Taken together, our data suggest that in androgen-dependent cell lines, addition of gefitinib in combination with bicalutamide results in concurrent dual inhibition of AR and EGFR/HER2 pathways. This causes a significant delay in the onset of EGFRdriven androgen independence. ' 2005 Wiley-Liss, Inc. Key words: prostate cancer; hormonal therapy; EGFR; androgenindependent tumorsIn industrialized countries, prostate cancer (PCa) is the most frequently occurring malignancy in men, representing the second highest cause of cancer-related death. PCa usually begins as an androgen-sensitive, androgen-dependent (AD), nonmetastatic cancer, which without intervention may follow a gradual transition into a highly metastatic and then androgen-insensitive (AI) variety. The androgen receptor (AR) is a nuclear receptor that cooperates with multiple proteins to exert its biologic function. Upon binding to the ligand testosterone/5 -dihydrotestosterone (DHT), the AR can bind to the androgen response element (ARE) on the 5 0 promoter of target genes, resulting in the modulation of cell growth. Until relatively recent times, endocrine response pathways in PCa were described solely in terms of the intracellular pathways used by the androgens and the subsequent destructive effects exerted on AR signaling by antihormonal treatments. 1 It is widely accepted that androgens promote tumor growth by binding to ARs and acting as nuclear transcription factors that regulate the expression of genes involved in cell proliferation and survival mechanisms. In contrast, hormonal therapies promote tumor regression either by reducing the amount of androgens available to the tumor cells or...

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confidence: 99%

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Festuccia

Gravina

Angelucci

et al. 2005

Intl Journal of Cancer

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“…The anti-proliferative effects of flutamide or irradiation were potentiated in combination with ZD1839. However, EGFR could be targeted only in a subgroup of prostate cancer patients (47). Use of drugs such as AMF that do not target a single molecule might be therefore justified.…”

Section: Discussionmentioning

confidence: 99%

Akacid-medical-formulation, a novel biocidal oligoguanidine with antitumor activity reduces S-phase in prostate cancer cell lines through the Erk 1/2 mitogen-activated protein kinase pathway

Neuwirt

Müller²,

Cavarretta³

et al. 2006

Int J Oncol

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Abstract. Oligomeric guanidines are highly efficient biocides against a broad spectrum of microorganisms. However, their antitumor effects have not been studied so far. We investigated an antiproliferative effect of Akacid-medical-formulation (AMF), a member of the oligoguanidine family of biocides, against solid cancer cell lines and primary cells by measuring [3 H]-thymidine incorporation. Additionally, we examined cell cycle distribution in two AMF-sensitive prostate cancer cell lines (DU-145, LNCaP) using flow cytometry. Finally, the influence of AMF on cell cycle regulatory molecules and intracellular kinase cascade-related signaling molecules was assessed. We found that AMF has variable antiproliferative effects on all tested cells. In DU-145 and LNCaP cells, flow cytometric studies showed a reduction of S-phase with a maximum extent of 24 and 58%, respectively. This was associated with a decrease in expression of cyclin D1, cyclindependent kinases 2 and 4, while having varying effects on expression of cyclin E and p27. Additionally, reduced phosphorylation of Erk1 and Erk2 was found, whereas expression of phospho-Akt1 remained unchanged. Herein we report for the first time that AMF exerts potent antiproliferative activity against various malignant cell lines, including those of prostate. We therefore recommend further investigation of the anticancer activity of this biocidal oliguanidine.

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“…Several groups have demonstrated the role of increased EGFR signaling in prostate carcinogenesis and progression (Sherwood et al, 1998;Ratan et al, 2003;Torring et al, 2003). We have recently reported the discovery of four somatic missense mutations in the tyrosine kinase domain of EGFR in prostate cancer patients (Douglas et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

et al. 2008

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While epidermal growth factor receptor (EGFR) dysregulation is known to play a critical role in prostate carcinogenesis, there has been no direct evidence indicating EGFR mutations induce tumorigenesis in prostate cancer. We previously identified four novel EGFR somatic mutations in the EGFR tyrosine kinase domain of prostate cancer patients: G735S, G796S, E804G and R841K. In this study, we investigated the oncogenic potential of these somatic mutations by establishing stable clonal NIH3T3 cells expressing these four mutations and WT EGFR to determine their ability to increase cell proliferation and invasion. In the absence of the EGF ligand, cell proliferation was readily increased in G735S, G796S and E804G mutants compared to WT EGFR. The addition of EGF ligand greatly increased cell growth and transforming ability of these same EGFR mutants. Matrigel invasion assays showed enhanced invasion with G735S, G796S and E804G mutants. Western blot analysis showed that these EGFR mutations enhanced cell growth and invasion via constitutive and hyperactive tyrosine phosphorylation and led to the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3) and Akt pathways. Our findings demonstrate the oncogenic activation of three novel EGFR somatic missense mutations in prostate cancer. Molecules that regulate the mechanisms of their oncogenic activation represent novel targets for limiting tumor cell progression, and further elucidation of these mutations will have utility in prostate cancer treatment.

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ErbB receptors: possible therapeutic targets in prostate cancer?

Cited by 30 publications

References 31 publications

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Akacid-medical-formulation, a novel biocidal oligoguanidine with antitumor activity reduces S-phase in prostate cancer cell lines through the Erk 1/2 mitogen-activated protein kinase pathway

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

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