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

Abstract

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.

Androgen deprivation of prostate cancer: Leading to a therapeutic dead end

“…Causal connections can be established between molecular changes in cellular pathways during ADT and the therapeutic failure of drugs targeting these pathways [43,57,67,77]. Clinical testing of new drugs in patients with CRPC can therefore not provide sufficient evidence, whether these drugs could be more effective before or during ADT.…”

“…erlotinib, gefitinib) or anti-ErbB antibodies (e.g. trastuzumab, pertuzumab) alone or in combination with docetaxel have not been encouraging in patients with CRPC [57][58][59][60][61][62].…”

Cellular prostatic acid phosphatase, a PTEN-functional homologue in prostate epithelia, functions as a prostate-specific tumor suppressor

“…Interestingly, recent reports suggest that the blocking of a single EGFR function can be compensated by the overexpression of alternative HERs, establishing an autocrine growth factor loop that maintains downstream signaling and PCa cellular proliferation [141–143]. Although substantial progress has been made toward understanding HER-2 dephosphorylation mechanism by PAcP; it is not yet known whether cPAcP is able to dephosphorylate other HER-2 family members such as EGFR and HER-3.…”

Emerging therapeutics targeting castration-resistant prostate cancer: the AR-mageddon of tumor epithelial–mesenchymal transition

“…This drug has been more extensively studied in non-small-cell lung cancer frequently harboring EGFR gene mutations that correlate with overexpression and consequently the therapeutic response to EGFR-TKIs [84]; none of the prostate cancer studies evaluated patients for EGFR mutation status. Other studies suggest that the EGFR inhibition can be circumvented by expression of alternative receptors in the EGFR family [85].…”