The Epidermal Growth Factor Receptor (EGFR) is over-expressed in multiple types of human cancer and is associated with more aggressive disease and lower survival rate. Therefore, EGFR is a popular target for many antitumor strategies. Current anti-EGFR therapies are only partially successful, mostly because the receptor is not absolutely essential for the survival of the cancer cell in which it is over-expressed.
Herein, we propose a new therapeutic approach, where the over-expression of EGFR is utilized to selectively introduce long synthetic dsRNA, poly Inosine/Cytosine (polyIC) into tumor cells. We hypothesize that targeted delivery of polyIC into cancerous cells, will lead to the activation of dsRNA-dependent pathways, and consequently induce tumor cell apoptosis and the secretion of cytokines and chemokines. Finally, the secreted compounds will recruit immune cells to the tumor area, thus causing a “bystander effect”, i.e. killing neighboring tumor cells, even those that do not over-express EGFR.
We have developed recombinant chimeric proteins which comprise the dsRNA binding domain of human PKR (dsRBD) fused to an EGFR binding molecule (EGF or EGFR affibody). These chimeras are able to selectively introduce poly IC into EGFR over-expressing cell lines. Treatment of MDA-MB-468 cells, which highly express EGFR, with the chimera/PolyIC complexes induced approximately 90% cell killing, while the chimera/PolyIC did not promote apoptosis in cell lines that do not express EGFR.
