Abstract 605: ErbB receptors and cisplatin resistance: the case for bladder cancer

Abstract

Abstract Nearly 30% of superficial bladder cancer (BC) cases develop into muscle invasive (MI) cases. With an initial discovery rate of 30% of MI cases, it is clear that treatment of MI disease should be a priority. Currently radical cystectomy is used in MI cases with neoadjuvant platinum based chemotherapy (PBC) highly recommended in the literature. With 1% of MI BC patients receiving this neoadjuvant therapy, metastases are common and PBC is the current treatment for these patients. However, cisplatin resistance is common in patients with MI BC leading to an average survival of only 15 months with a 5 year survival of 20%. Increased expression of epidermal growth factor receptor (EGFR) and related receptors ErbB2 and ErbB3 in BC is well documented. These receptors control cell growth and survival and several EGFR ligands are present in normal human urine. Thus we hypothesized that these receptors may play a role in BC resistance to PBC. EGFR family inhibition (EGFRi) has been investigated in conjunction with PBC in clinical trials. However, these trials did not show and increased benefit due to many of these patients having previously failed PBC therapy, EGFR/ErbB status not being part of the inclusion criteria, and frequent resistance to EGFRi in this patient population. We wanted to determine a mechanism for cisplatin and EGFRi resistance with the hypothesis that this could lead to novel therapeutics for MI BC. The BC cell lines T24, TCCSUP, J82 and RT4 were assayed for cisplatin sensitivity by flow cytometry. The TCCSUP and J82 cells were deemed cisplatin sensitive due to increased apoptosis when treated with cisplatin. The T24 and RT4 cells showed no apoptosis increase and were deemed to be cisplatin resistant. MTT and clonogenic assay determined that cisplatin resistant cells were also resistant to EGFRi. Similarly, cisplatin sensitive cells were sensitive to EGFRi. Additionally, it was determined that treating all cell lines with cisplatin and dacomitinib had a synergistic effect on reducing cell proliferation. Activation of EGFR, ErbB2 and ErbB3 was assayed by western blotting. Cisplatin sensitive cells underwent EGFR driven ErbB activation while cisplatin resistant cells underwent ErbB3 driven ErbB activation. Additionally, activation of EGFR Y845, Y1045, and Y1068 was increased by cisplatin in resistant cells. These results indicate that EGFRi and cisplatin, while working in parallel pathways, can influence one another. EGFR binding may be a prognostic marker for response to EGFRi. If EGFR binds primarily with ErbB2, the cells would likely respond to EGFRi; but, if EGFR binds primarily with ErbB3, the cells would likely be EGFRi resistant. Activation of EGFR Y845 (a Src binding site) may determine the preferential ErbB binding. EGFR Y845 activation may be blocked by EGFRi thus abrogating the effect of cisplatin and returning the cells to a cisplatin sensitive state. Citation Format: Benjamin Asher Mooso, Duanna Challenger, Paramita Ghosh. ErbB receptors and cisplatin resistance: the case for bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 605. doi:10.1158/1538-7445.AM2014-605