CD46 protects the bladder cancer cells from cetuximab-mediated cytotoxicity

Abstract

Epidermal growth factor receptor (EGFR) is an effective target for those patients with metastatic colorectal cancers that retain the wild-type RAS gene. However, its efficacy in many cancers, including bladder cancer, is unclear. Here, we studied the in vitro effects of cetuximab monoclonal antibodies (mAbs) targeting EGFR on the bladder cancer cells and role of CD46. Cetuximab was found to inhibit the growth of both colon and bladder cancer cell lines. Furthermore, cetuximab treatment inhibited AKT and ERK phosphorylation in the bladder cancer cells and reduced the expression of CD46 membrane-bound proteins. Restoration of CD46 expression protected the bladder cancer cells from cetuximab-mediated inhibition of AKT and ERK phosphorylation. We hypothesized that CD46 provides protection to the bladder cancer cells against mAb therapies. Bladder cancer cells were also susceptible to cetuximab-mediated immunologic anti-tumor effects. Further, cetuximab enhanced the cell killing by activating both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in bladder cancer cells. Restoration of CD46 expression protected the cells from both CDC and ADCC induced by cetuximab. Together, CD46 exhibited a cancer-protective effect against both direct (by involvement of PBMC or complement) and indirect cytotoxic activity by cetuximab in bladder cancer cells. Considering its clinical importance, CD46 could be an important link in the action mechanism of ADCC and CDC intercommunication and may be used for the development of novel therapeutic strategies.

Complement regulatory protein CD46 promotes bladder cancer metastasis through activation of MMP9

“…CD46 typically acts as a protector against complement-mediated cytotoxicity in cells. Previous studies reported that CD46 also shields cancer cells from the indirect cytotoxic effects of cetuximab (an EGFR inhibitor), by modulating AKT and ERK phosphorylation in bladder cancer cells ( 16 ). The direct role of intracellular CD46 in cancer cells, however, remains poorly understood.…”

“…Additionally, CD46 contributes to the tumorigenesis and development of bladder cancer ( 15 ). Our previous research demonstrated that restoring CD46 expression in bladder cancer cells conferred protection against cetuximab-mediated inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation ( 16 ). This restoration also protected cells from complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity induced by cetuximab.…”

“…Despite significant progress in understanding CD46, a number of aspects of its functions and the molecular mechanisms involved in cancer cell metastasis remain unclear. Our previous research demonstrated that CD46 is highly expressed in bladder cancers, where it helps protect cancer cells from various cytotoxic insults ( 16 , 29 ). Moreover, CD46 appears to influence cell migration by altering the expression of several cytoskeletal proteins ( 30 ).…”

The complement regulatory protein CD46 serves as a novel biomarker for cervical cancer diagnosis and prognosis evaluation

“…Currently, targeting CD46 as a therapeutic strategy in cancers has attracted increasing attention to overcome the poor therapeutic efficacy of conventional cancer treatments, including the inhibition of CD46 expression ( 11 , 29 – 31 ), neutralizing (blocking) mAbs ( 30 – 32 ), anti-CD46 antibody−drug conjugates (CD46-ADCs) ( 21 , 33 – 36 ), and oncolytic virotherapy ( 37 – 42 ). It has been demonstrated that targeted downregulation of CD46 expression by siRNA in vitro increases the sensitivity of cancer cells to CDC ( 11 ).…”

Recent Pre-Clinical Advancements in Nuclear Medicine: Pioneering the Path to a Limitless Future

“…CD46 is a membrane-bound complement regulatory protein that protects the cells from complement-cytotoxic death and plays a key role in metastatic disease [157,158]. YS5, an antibody directed against CD46, has shown high therapeutic potential in addressing both adenocarcinoma and neuroendocrine PC [156].…”