Neuregulin Expression Modulates Clinical Response to Trastuzumab in Patients With Metastatic Breast Cancer

Álava, Enrique de; Ocaña, Alberto; Abad, Mónica Viñarás; Montero, Juan Carlos; Esparı́s-Ogando, Azucena; Rodrı́guez, César; Otero, Ana Pastora; Hernández, Teresa; Cruz, Juan Jesús; Pandiella, Atanasio

doi:10.1200/jco.2006.08.6850

Cited by 53 publications

(50 citation statements)

References 22 publications

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“…There is growing evidence that tumor cells might circumvent the effects of EGFR inhibitors through the promotion of HER3/HER2 heterodimerization and the activation of the PI3K/Akt pathway (38,45,61,(68)(69)(70). Our results confirm the relevance of HER3 in mediating resistance to EGFR TKIs in androgen-independent prostate cancer cells.…”

Section: Discussionsupporting

confidence: 78%

Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

Carrión-Salip

Panosa

Menendez

et al. 2012

International Journal of Oncology

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Abstract. The deregulation of the epidermal growth factor receptor (EGFR) pathway plays a major role in the pathogenesis of prostate cancer (PCa). However, therapies targeting EGFR have demonstrated limited effectiveness in PCa. A potential mechanism to overcome EGFR blockade in cancer cells is the autocrine activation of alternative receptors of the human EGFR (HER) family through the overexpression of the HER receptors and ligands. In the present study, we were interested in analyzing if this intrinsic resistance mechanism might contribute to the inefficacy of EGFR inhibitors in PCa. To this end, we selected two androgen-independent human prostate carcinoma cell lines (DU145 and PC3) and established DU145 erlotinib-resistant cells (DUErR). Cells were treated with three EGFR inhibitors (cetuximab, gefinitib and erlotinib) and the sensitivity to each treatment was assessed. The gene expression of the four EGFR/HER receptors and seven ligands of the HER family was analyzed by real-time PCR prior to and after each treatment. The receptors expression and activation were further characterized by flow cytometry and western blot analysis. EGFR inhibition rapidly induced enhanced gene expression of the EGF, betacellulin and neuregulin-1 ligands along with HER2, HER3 and HER4 receptors in the DU145 cells. In contrast, slight changes were observed in the PC3 cells, which are defective in the phosphatase and tensin homolog (PTEN) tumor suppressor gene. In the erlotinib-resistant DUErR cells, the expression of HER2 and HER3 was increased at mRNA and protein levels together with neuregulin-1, leading to enhanced HER3 phosphorylation and the activation of the downstream PI3K/Akt survival pathway. HER3 blockage by a monoclonal antibody restored the cytostatic activity of erlotinib in DUErR cells. Our results confirm that the overexpression and autocrine activation of HER3 play a key role in mediating the resistance to EGFR inhibitors in androgen-independent PCa cells.

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Section: Discussionsupporting

confidence: 78%

Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

Carrión-Salip

Panosa

Menendez

et al. 2012

International Journal of Oncology

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“…In the early stages of trastuzumab clinical development in MBC, it was noted that HER-2-negative tumors by IHC rarely responded to the antibody, and that, if all patients were treated, the low response rate in HER-2-negative cases would significantly dilute the enhanced response rate in HER-2-positive cases and mask the overall clinical benefit of the novel therapeutic. One intriguing possible predictor of trastuzumab benefit in HER-2-negative breast cancer is the preliminary observation that HER-2-negative tumors that overexpress neuregulin, an activating ligand for HER-4, are inhibited by HER-2-targeted therapy [288]. Alternatively, it is also possible (although unprece-dented) that a drug may have no significant anticancer activity in a particular disease subset in the metastatic stage (i.e., HER-2-normal cancers), but may have antitumor activity against the same subset in the micrometastatic stage.…”

Section: Trastuzumab Administration and Pharmacokineticsmentioning

confidence: 99%

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

et al. 2009

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1. Contrast the current strengths and limitations of the three main slide-based techniques (IHC, FISH, and CISH) currently in clinical use for testing breast cancer tissues for HER-2 status.2. Compare the efficacy of trastuzumab-and lapatinib-based regimens in the adjuvant and metastatic settings as reported in published clinical trials and regulatory approval databases.3. Contrast the list of biomarkers that have been associated with clinical resistance to trastuzumab and lapatinib and describe their current level of validation.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTThe human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ

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“…Increasing evidence indicates that NRGs may have a relevant role in cancer. Thus, expression of NRGs has been described in several tumour types (Breuleux, 2007;Montero et al, 2008), and has been linked to the response to trastuzumab in breast cancer (Yuste et al, 2005;de Alava et al, 2007). In addition, expression of transmembrane NRGs in breast cancer cells activates ErbB2/ HER2, and favours their proliferation in vitro (Yuste et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer

et al. 2010

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The Neuregulins and their receptors, the ErbB/HER subfamily of receptor tyrosine kinases, have critical roles in animal physiology, and their deregulation is frequent in cancer. Here we report the identification of the guanine nucleotide exchange factor, phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 (P-Rex1), as a novel mediator in signalling by ErbB/HER receptors. P-Rex1 was formerly described as a phosphoinositide 3-kinase and Gbc activated protein that regulates Rac function. We define how ErbB/HER receptors regulate P-Rex1 function, which involves dephosphorylation of inhibitory residues, and phosphorylation of activating residues of P-Rex. The net balance resulting from activation of this phosphorylation/dephosphorylation cycle of P-Rex1 favours Rac activation. Molecular and biological studies indicated that P-Rex1 phosphorylation regulated the proliferation of breast cancer cells, and P-Rex1 knockdown affected their migration or invasiveness, as well as their in vivo tumourigenic potential. Moreover, as we found correlation between high P-Rex1 expression and poor patient outcome in breast cancer, P-Rex1 targeting may be therapeutically relevant in cancer.

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Neuregulin Expression Modulates Clinical Response to Trastuzumab in Patients With Metastatic Breast Cancer

Abstract: We suggest that the spectrum of patients who may benefit from trastuzumab-based therapies may be widened to include patients with metastatic breast cancer without HER-2 amplification but who express transmembrane NRGs.

Cited by 53 publications

References 22 publications

Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer

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