Potentiation of antitumour activity of docetaxel by combination with trastuzumab in a human prostate cancer xenograft model and underlying mechanisms

Abstract

Antitumour activity of docetaxel (Taxotere s ) in hormone-dependent (HD) and hormone-independent (HID) prostate cancer PAC120 xenograft model was previously reported, and its level was associated with HER2 protein expression. In the present study, we evaluate the antitumour effects of docetaxel combined with trastuzumab (Herceptin s ), an anti-HER2 antibody. Although trastuzumab alone had no effect on tumour growth, it potentiated the antitumour activity of docetaxel in HD tumours and more strongly in HID variants. Using the HID28 variant, we show that docetaxel treatment of tumour-bearing mice induces an increased HER2 mRNA expression of the tyrosine kinase receptor of 25-fold 24 h after docetaxel treatment, while HER2 protein and p-AKT decreased. This was followed by an increase of HER2 protein 3 days (two-fold) after docetaxel treatment and by a strong HER2 release in the serum of treated mice; expression of phospho-ERK, p27, BCL2 and HSP70 concomitantly increased. Similar molecular alterations were induced by docetaxel plus trastuzumab combination, except for that there was a transient and complete disappearance of AR and HSP90 proteins 24 h after treatment. We show that in addition to its known effects on tubulin and mitotic spindles, docetaxel induces complex signalisation pathway mechanisms in surviving cells, including HER2, which can be pharmacologically targeted. This study suggests that the docetaxel/trastuzumab combination may prove an effective therapeutic approach for HER2-expressing hormone-refractory prostate cancer. Escape from androgen ablation therapy is a constant feature of prostate cancer progression, leaving patients with few therapeutic options. Hormone-refractory prostate cancer (HRPC) was regarded as chemoresistant, until the recent demonstration of taxane activity (Petrylak et al, 1999). A preclinical in vivo study using our PAC120 model of hormone-dependent (HD) human prostate cancer xenograft confirmed these data (de Pinieux et al, 2001;Oudard et al, 2003). A randomised phase II study demonstrated the efficacy of docetaxel-based chemotherapy vs a mitoxantroneprednisone combination, significantly decrease PSA and prolongs time to progression of metastatic HRPC patients (Oudard et al, 2005). Despite these encouraging preclinical and clinical data, the therapeutic efficacy of taxane-based chemotherapy of HRPC remains modest. A better knowledge of the mechanisms of tumour hormonal escape and of key molecular targets is needed to design more effective combination therapies for HRPC.Several preclinical studies have implicated the ERBB family of tyrosine kinase receptors, especially HER2, in the progression of prostate cancer to a hormone-refractory state. The CWR22 hormone-independent prostate cancer xenograft expresses HER2 and its growth is inhibited in vivo by an anti-HER2 antibody (Agus et al, 1999;Mendoza et al, 2002). Increased hormone independence in prostate cancer cells was associated with androgen receptor (AR) phosphorylation mediated by transfected HER2 (Craft et al, 1999;Yeh e...

Bevacizumab plus 5-fluorouracil induce growth suppression in the CWR-22 and CWR-22R prostate cancer xenografts

“…Our present study shows that bevacizumab, when given together with 5-FU, was far more effective than monotherapy in treatment of prostate cancer. Our data, coupled with previous reports (20,31,39), suggest that in prostate cancer, targeting different pathways using both biological and cytotoxic compounds is needed. The safety and efficacy of bevacizumab/docetaxel/estramustine combination for hormone-refractory prostate cancer have been reported (reviewed in ref.…”

“…Although our preclinical data hold much promise, clinical trials are needed to determine whether bevacizumab/5-FU is as effective as docetaxel/prednisone (reviewed in ref. 6) or docetaxel/ trastuzumab combination (39) in therapy for metastatic hormone-refractory prostate cancer.…”

Inhibition of the Ras-Net (Elk-3) Pathway by a Novel Pyrazole that Affects Microtubules

“…Furthermore, we found that docetaxel has a slight positive effect on c-fos expression in contrast to XRP44X. Similar effects on c-fos expression and associated activation of Erk-1/2 have been described recently (39,40). Taxoids and microtubule-destabilizing agents have opposite effects on c-myc oncogene expression in some cell types (41) through mechanisms involving nuclear factor-nB (NF-nB; ref.…”

Low Level Her2 Overexpression Is Associated with Rapid Tumor Cell Proliferation and Poor Prognosis in Prostate Cancer

“…Moreover, the effect of trastuzumab was limited in few clinical prostate cancer trials (47)(48)(49). It could be argued, nevertheless, that different dosages of trastuzumab or combination therapy (50) would be required to be effective in prostate cancers with relatively low levels of overexpression. Independent of this, it might be interesting to include prostate cancer patients in clinical studies using new generations of more efficient anti-Her2 drugs such as the anti-Her2 recombinant humanized monoclonal antibody 2C4 or antisense approaches (51,52).…”