Abstract
Members of the human epidermal growth factor receptor (HER) family play a significant role in bladder cancer progression and may underlie the development of chemotherapy resistance. Dacomitinib is an irreversible tyrosine kinase inhibitor with structural specificity for the catalytic domains of epidermal growth factor receptor (EGFR), HER2 and HER4 that has exhibited vigorous efficacy against other solid tumors. We evaluated the antitumor activity of dacomitinib in human bladder cancer cell lines expressing varying levels of HER family receptors. These cell lines also were established as bladder cancer xenografts in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice to assess dacomitinib activity in vivo. Significant cytotoxic and cytostatic effects were noted in cells expressing elevated levels of the dacomitinib target receptors with apoptosis and cell cycle arrest being the predominant mechanisms of antitumor activity. Cells expressing lower levels of HER receptors were much less sensitive to dacomitinib. Interestingly, dacomitinib was more active than either trastuzumab or cetuximab in vitro, and exhibited increased growth inhibition of bladder tumor xenografts compared with lapatinib. Pharmacodynamic effects of dacomitinib included decreased E-cadherin (E-cad) expression, reduction of EGFR and extracellular signal-regulated kinase (ERK) phosphorylation and reduced mitotic count. Dacomitinib also inhibited tumor growth in a chemotherapy-resistant xenograft and, when combined with chemotherapy in a sensitive xenograft, exhibited superior antitumor effects compared with individual treatments. Evaluation in xenograft-bearing mice revealed that this combination was broadly feasible and well tolerated. In conclusion, dacomitinib exhibited pronounced activity both as a single agent and when combined with chemotherapy in human bladder cancer models. Further investigation of dacomitinib in the preclinical and clinical trial settings is being pursued.
Highlights
In the last two decades there has been little progress in the development of systemic therapies in bladder cancer, and the identification of new and effective treatments is critically needed
Reagents Dacomitinib was provided by Pfizer (New York, NY, USA); cetuximab was provided by Eli Lilly (Indianapolis, Indiana, USA); trastuzumab, cisplatin and gemcitabine were provided by the University of Michigan Comprehensive Cancer Center Pharmacy; and lapatinib was purchased from LC Laboratories (Woburn, MA, USA)
We noted that UM-UC-6 and UM-UC-9 expressed relatively higher levels of the dacomitinib targets, epidermal growth factor receptor (EGFR), HER2 and HER4 while UM-UC-3 exhibited lower levels of EGFR and HER2 and undetectable expression of HER4 (Figure 1)
Summary
In the last two decades there has been little progress in the development of systemic therapies in bladder cancer, and the identification of new and effective treatments is critically needed. Overexpression of HER family members and activation of downstream signaling pathways have been implicated in the development and progression of several human cancers, including bladder cancer [1,6,7,8,9]. EGFR and HER2 overexpression has been correlated with higher grade, stage, disease progression and shorter survival in bladder cancer patients [10,11,12,13,14,15,16]. Data suggest that HER-downstream signaling is associated with progression of bladder cancer and the development of resistance to chemotherapy [9,17,18,19]. Preclinical studies support the use of HER inhibitors [17,18,19, 22,23,24]; these compounds have not exhibited meaningful clinical efficacy in patients with bladder cancer [25,26]
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