Lapatinib, a dual inhibitor of ErbB-1/-2 receptors, enhances effects of combination chemotherapy in bladder cancer cells

Abstract

Abstract. Survival rate of patients diagnosed with the invasive form of bladder cancer is low suggesting an urgent need to implement novel treatments. GTC (gemcitabine, paclitaxel and cisplatin) is a new chemotherapeutic regimen, which has shown promise in clinical trials. Given that receptor tyrosine kinases of the ErbB family are overexpressed in a high proportion of metastatic bladder tumours, approaches involving small-molecule inhibitors of ErbB receptors in combination with conventional cytostatic drugs are of potential interest. Here, we show that the dual inhibitor of ErbB receptors, lapatinib, enhances cytostatic and induces cytotoxic effects of GTC in two bladder cancer cell lines which differ with regard to expression levels of proteins taking part in the ErbB pathway. Lapatinib inhibited phosphorylation of ErbB receptors and also reduced the level of phosphorylated AKT. Flow cytometry analysis demonstrated that GTC treatment affects cell cycle distribution differently in the presence or absence of lapatinib. In RT112 cells, which express high levels of ErbB receptors and harbour wild-type p53, combined GTC/lapatinib treatment resulted in the phosphorylation of p53 at Ser46 and accumulation of sub-G 1 cell populations. Our data indicate that a combinatorial approach involving GTC and lapatinib may have therapeutic potential in a subset of bladder tumours depending on the genetic context. IntroductionBladder cancer is a worldwide disease with poor clinical outcome, especially among patients with the muscle invasive form of the disease (1). Several combinations of chemotherapeutic agents are used in treatment of metastatic transitional cell carcinoma (TCC) of the bladder. The combination of methotrexate, vinblastine, doxorubicin and cisplatin was previously considered the 'gold standard' chemotherapy treatment of TCC, although the median survival was only one year (2). Administration of the gemcitabine and cisplatin regimen has resulted in decreased toxicity, but has not improved survival rates (3). At present, a combination of gemcitabine, paclitaxel (taxol) and cisplatin (GTC) with median survival of 22 months is considered as a promising approach (4). In view of the continuing modest survival rates, novel targeted therapies for the treatment of advanced TCC of the bladder are urgently required. Much interest currently centres on modifying the activity of epidermal growth factor receptor (EGFR) family members (5-7). This family, which has been implicated in human cancers, comprises four receptors, ErbB-1 (HER1, EGFR), ErbB-2 (HER2), ErbB-3 (HER3) and ErbB-4 (HER4) (8). High expression of ErbB-1/ErbB-2, which has been described in TCC of the bladder, is an independent predictor of reduced survival (9-12). In contrast, high expression of ErbB-3/ErbB-4 is associated with favourable clinical outcome in TCC patients (13,14).The ErbB receptors are composed of an extracellular ligand-binding region, transmembrane domain, and a cytoplasmic region containing a tyrosine kinase domain and autophosphorylation sit...

Lapatinib-Loaded Nanocapsules Enhances Antitumoral Effect in Human Bladder Cancer Cell

“…In addition, after NC-LAP treatment, it was possible to observe an almost complete inhibition of cells with reproductive potential. Our data agrees with the literature, since it has already been reported that lapatinib strongly inhibited cell proliferation and induced cell cycle G1 arrest and apoptosis in bladder cancer cells (17, 47).…”

“…HER1 and HER2 receptors have shown altered expression in several types of cancers, including bladder cancer (16, 17). EGFR have in common an extracellular binding domain, a transmembrane portion and an intracellular domain of tyrosine kinase (18, 19).…”

Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy

“…Lapatinib also provoked an anti-tumour effect in the canine TCC-engrafted mouse model with minimal side effects. This research is very promising, especially considering that the anti-tumor activity of lapatinib was also observed in human bladder cancer cell lines ( McHugh et al, 2009 ), wherein it exhibited overexpression of HER2 determined by an immunochemistry range from 8% up to 80% ( Jimenez et al, 2001 ; Powles et al, 2017 ). Unfortunately, treatment of human bladder cancer patients using lapatinib ( Figure 1 : 8) during a stage III randomized trial was unsuccessful ( Powles et al, 2017 ).…”