Results from a monocentric phase II trial of erlotinib in patients with metastatic prostate cancer

Gravis, Gwénaëlle; Bladou, Franck; Salem, Naji; Gonçalvès, Anthony; Esterni, Benjamin; Walz, Jochen; Bagattini, S.; Marcy, M.; Brunelle, Serge; Viens, Patrice

doi:10.1093/annonc/mdn174

Cited by 59 publications

(38 citation statements)

References 28 publications

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“…However, the results of clinical trials involving EGFR inhibitors have revealed a reduced efficacy in PCa patients (27)(28)(29)35). The cooperative nature of the HER family might play an important role in the low effectiveness of drugs targeting EGFR as the co-expression of different HER members in the cancer cell can activate parallel signaling pathways to circumvent the inhibition of this specific receptor (6,48).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the HER family members have been considered as potential therapeutic targets in prostate cancer. However, despite the blockade of EGFR or HER2 having demonstrated an ability to inhibit the proliferation of human prostate tumor cells (24)(25)(26), the clinical results have revealed only slight benefit of the HER-targeted therapy in patients with androgen-independent PCa both when EGFR inhibitors were administered as monotherapy or in association with antiandrogens or chemotherapeutics (27)(28)(29)(30)(31)(32)(33). The molecular mechanism underlying the low efficiency of EGFR inhibitors in human PCa remains to be elucidated.…”

Section: Androgen-independent Prostate Cancer Cells Circumvent Egfr Imentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Androgen-independent Prostate Cancer Cells Circumvent Egfr Imentioning

confidence: 99%

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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“…During the last year, several clinical trials have reported various degrees of clinical benefits following treatment with TKIs for this patient category (11)(12)(13)20,21). Sorafenib has demonstrated some clinical effects in three independent phase II trials in patients with hormone refractory, metastatic prostate cancer (11)(12)(13); however the underlying molecular sorafenib-induced antitumoral effects are poorly studied for this disease.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib induces apoptosis and autophagy in prostate cancer cells in vitro

et al. 2010

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Abstract. The multiple tyrosine kinase inhibitor sorafenib has recently demonstrated clinical effects in patients with androgen-independent prostate cancer. These observations provided the rational for investigating the anti-tumoral properties of this compound on prostate cancer cell lines at the molecular level. Two hormone refractory (PC3 and DU145) and one hormone responsive cell line (22Rv1) were used. By use of a panel of cell biology techniques such as immunoblotting, flow cytometry and immunocytochemistry, effects on the MAPK pathway and induction of apoptosis and autophagy were evaluated. We demonstrate that sorafenib reduced cell viability in a dose-dependent manner, induced apoptosis and inactivated the MAPK pathway. Moreover, we show for the first time, that sorafenib treatment of prostate cancer cells also induces cellular autophagy. This feature is in accordance with the anticancer potential of sorafenib and adds another important effector mechanism of this compound. These observations may open potentially interesting treatment combinations that may augment the effect of sorafenib, either by drugs that promote autophagy such as the rapalogues, or by combining sorafenib with compounds that specifically inhibit the autophagic process.

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“…So far despite some promising preclinical results, EGFR inhibition in mCRPC has mainly resulted in negative experiences. Single-agent trials with the EGFRtyrosine kinase inhibitors (TKI) gefitinib (21) and erlotinib (22,23) or the monoclonal antibody panitumumab (24) did not achieve any significant PSA response. Two other trials with cetuximab in combination with chemotherapy for patients with advanced prostate cancer have been presented earlier (25,26): the combination of cetuximab with doxorubicin was associated with minimal PSA declines (25) and the combination of cetuximab with mitoxantrone did not show a benefit when compared with mitoxantrone alone (26).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Cetuximab in Metastatic Castration-Resistant Prostate Cancer Might Depend on EGFR and PTEN Expression: Results from a Phase II Trial (SAKK 08/07)

Cathomas

Rothermundt

Klingbiel

et al. 2012

Clinical Cancer Research

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Purpose: The EGF receptor (EGFR) is overexpressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target. The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer.Experimental Design: Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II trial. Treatment consisted of docetaxel (75 mg Results: Thirty-eight patients were enrolled at 15 Swiss centers. Median age was 68 years and median PSA was 212 ng/mL. PFS at 12 weeks was 34% [95% confidence interval (CI), 19%-52%], PFS at 24 weeks was 20%, and median overall survival (OS) was 13.3 months (95% CI, 7.3-15.4). Seven patients (20%) had a confirmed !50% and 11 patients (31%) a confirmed !30% PSA decline. About 47% of enrolled patients experienced grade 3 and 8% grade 4 toxicities. A significantly improved PFS was found in patients with overexpression of EGFR and persistent activity of PTEN.Conclusions: EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC. A potential correlation between EGFR overexpression, persistent expression of PTEN, and EGFR inhibition should be investigated further.

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Results from a monocentric phase II trial of erlotinib in patients with metastatic prostate cancer

Abstract: Erlotinib demonstrated an improvement in clinical benefit. Future directions should include evaluating its use in less advanced prostate cancer.

Cited by 59 publications

References 28 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

Sorafenib induces apoptosis and autophagy in prostate cancer cells in vitro

Efficacy of Cetuximab in Metastatic Castration-Resistant Prostate Cancer Might Depend on EGFR and PTEN Expression: Results from a Phase II Trial (SAKK 08/07)

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