CD46 and Oncologic Interactions: Friendly Fire against Cancer

Abstract

One of the most challenging aspects of cancer therapeutics is target selection. Recently, CD46 (membrane cofactor protein; MCP) has emerged as a key player in both malignant transformation as well as in cancer treatments. Normally a regulator of complement activation, CD46 is co-expressed as four predominant isoforms on almost all cell types. CD46 is highly overexpressed on a variety of human tumor cells. Clinical and experimental data support an association between increased CD46 expression and malignant transformation and metastasizing potential. Further, CD46 is a newly discovered driver of metabolic processes and plays a role in the intracellular complement system (complosome). CD46 is also known as a pathogen magnet due to its role as a receptor for numerous microbes, including several species of measles virus and adenoviruses. Strains of these two viruses have been exploited as vectors for the therapeutic development of oncolytic agents targeting CD46. In addition, monoclonal antibody-drug conjugates against CD46 also are being clinically evaluated. As a result, there are multiple early-phase clinical trials targeting CD46 to treat a variety of cancers. Here, we review CD46 relative to these oncologic connections.

Treating Prostate Cancer by Antibody–Drug Conjugates

“…Basing on the evidence that the expression of CD46 is high in prostate cancer tissue and CRPC but low in normal tissues [ 65 ], CD46 represents an ideal target for ADC therapy [ 66 ]. CD46 ADC has demonstrated to potently and selectively kill both adenocarcinoma and NEPC cells both in vitro and in vivo [ 66 ].…”

Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections

“…CD46 is emerging as a therapeutic oncologic target (reviewed in Ref. [ 11 ]). While CD46 expression level on peripheral blood mononuclear cells and granulocytes is ∼10 000/cell, tumor-derived cells and cell lines range from 100 000–250 000/cell (reviewed in Refs.…”

“…The most remarkable example of overexpression may be in relapsed multiple myeloma in which CD46 expression is increased up to 14-fold in patients who have the region on chromosome 1q carrying CD46 genomically amplified (reviewed in Ref. [ 11 ]). Additionally, species of AdV and MV (targeting CD46) are being exploited as engineered, modified vectors for wide-ranging therapeutic interventions.…”

“…[ 66 ]). Additional therapeutic trials targeting CD46 include those for oncology [ 11 , 12 ], HIV, Ebola virus and Zika virus ([ 11 ] and reviewed in Refs. [ 61 •• , 67 , 68 ]).…”

“…Second, because of its overexpression on a variety of human tumors, CD46 is emerging as a key player in both malignant transformation and in cancer therapeutics (reviewed in Refs. [ 11 , 12 , 13 ]). Third, CD46 signaling via motifs in its tails may critically impact cell behavior.…”