My journey from tyrosine phosphorylation inhibitors to targeted immune therapy as strategies to combat cancer

Abstract

Since the 1980s there has been a drive toward personalized targeted therapy for cancer. "Targeted cancer therapy" originally focused on inhibiting essential tumor survival factors, primarily protein tyrosine kinases. The complexity and rapid mutability of tumors, however, enable them to develop resistance to tyrosine kinase inhibitors (TKIs), even when these are multitargeted or applied in combination. This has led to the development of targeted cancer immunotherapy, to enhance immune surveillance against the tumor. In this paper, we provide a personal view of the development of targeted therapy, from TKIs to targeted immunotherapy.

Keywords: cancer; immunotherapy; targeted therapy; tyrosine kinase; tyrphostin.

Fig. 1.

The growing arsenal of anticancer therapeutics. Effective control of cancer requires appropriate combinations. Immunotherapy has the potential to hunt out distant metastases and provide long-term solutions.

Fig. 2.

Vectors that carry PolyIC, a synthetic dsRNA. The vectors we designed are built from three parts: (i) A polyIC binding moiety, such as polyethyleneimine (PEI). PEI also functions as a “proton sponge,” causing the endosome to swell and burst, releasing the dsRNA into the cytoplasm, where it interacts with its molecular targets. (ii) A linker, such as PEG. (iii) A homing ligand or antibody, which guides the vector to the appropriate cells. The ligand is aimed at a receptor that is overexpressed on the cancer cell.

Fig. 3.

Possible mechanisms of action of targeted polyIC. Targeted polyIC is internalized upon activation of the targeted receptor, which is overexpressed on the tumor cells. The double-stranded polyIC is expected to activate TLR3, which is mainly found in endosomes. TLR3, via its adaptor Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), induces the phosphorylation of IFN Regulating Factor 3 (IRF3) and its translocation into the nucleus, as well as the phosphorylation of IKK and nuclear translocation of NFκB. IRF3 and NF-κB activate transcription of IFN-α, IFN-β, and proinflammatory cytokines such as TNF-α. Furthermore, upon endosomal release, polyIC can activate the cytoplasmic dsRNA receptors, PKR, MDA-5, and RIG-1. PKR and TLR3 also activate the MAPK pathway, resulting in activation of AP-1 and apoptosis. PKR directly phosphorylates eIF2-α, arresting protein synthesis. IFN production leads to further feedback activation of the “antiviral” response. Thus, polyIC induces the production of type I IFNs and inflammatory cytokines, leading to apoptosis and immune recruitment by multiple pathways.

Fig. 4.

The advantages of the targeted polyIC approach to tumor therapy.