Small-molecule protein kinase inhibitors and their effects on the immune system: implications for cancer treatment

Abstract

Oncogenic signaling pathways have emerged as key targets for the development of small-molecule inhibitors, with several protein kinase inhibitors already in clinical use for cancer patients. In addition to their role in tumorigenesis, many of the molecules and signaling pathways targeted by these inhibitors are also important in the signaling and interaction of immune cells, such as T cells and dendritic cells. Not surprisingly, there is increasing evidence that many of these inhibitors can have a substantial impact on immune function, both stimulating and downregulating an immune response. In order to illustrate the important role of signaling molecule inhibition in the modulation of immune function, we will discuss the exemplary pathways MAPK, AKT-PI3K-mTOR and VEGF-VEGFR, as well as selected small-molecule inhibitors, whose impact on immune cells has been studied more extensively.

Fig. 1

Small molecule kinase inhibitors and their targets in tumor cells: Signal transduction cascades initiated by growth factors receptors such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptors (VEGFRs, VEGFR-1, VEGFR-2, and VEGFR-3), platelet-derived growth factor receptor (PDGFR) alpha and beta, insulin-like growth factor receptor (IGFR) regulate cancer cell proliferation, metastasis, adhesion, apoptosis, invasion, and angiogenesis. The MAPK and PI3K/AKT/mTOR pathways shown here are prominent examples of the complex network of signaling pathways and are targeted by protein kinase inhibitors either directly (e.g. by Temsirolimus) or by agents acting mainly upstream, on the growth factor receptor level (sorafenib, sunitinib, imatinib). EGFR: EGF receptor; ERK: Extracellular signal-regulated kinase; IGFR: IGF receptor; PDGFR: PDGF receptor; VEGFR: VEGF receptor.

Fig. 2

Small molecule kinase inhibitors and their targets in T cells: Many signaling molecules and pathways targeted by small molecule kinase inhibitors are also present in T cells. Therefore, these inhibitors have the potential to mediate downstream effects such as cell proliferation and effector functions (cytokine production, cell lysis). Illustrated here are the T cell receptor (TCR)/peptide/MHC interface and some of the key signaling pathways associated with the TCR and other T cell surface receptors such as CD25 (the IL-2 receptor) and CD28 (costimulatory receptor). ERK: Extracellular signal-regulated kinase; TCR: T-cell receptor.

Fig. 3

Small molecule kinase inhibitors and their targets in antigen presenting cells: Many signaling molecules and pathways targeted by small molecule kinase inhibitors are also present in antigen presenting cells (monocytes, macrophages, Dendritic cells, B cells). Selected signaling pathways downstream of Toll Like Receptors (TLRs) located in the surface membrane and intracellular compartment membranes are illustrated. Downstream TLR signaling molecules such as MyD88 and TRAF6 can be directly targeted by protein kinase inhibitors such as sorafenib. These adaptor proteins/signaling molecules also interact with the PI3K/AKT/mTOR and the MAPK pathways. As a result, small molecule kinase inhibitors can modulate DC function such as cytokine production and expression of costimulatory molecules. ERK: Extracellular signal-regulated kinase; TLR: Toll-like receptor.