Biological Hallmarks and Emerging Strategies to Target STAT3 Signaling in Multiple Myeloma

Abstract

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by an abnormal accumulation of plasma cells in the bone marrow. Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that modulates the transcription of multiple genes to regulate various principal biological functions, for example, cell proliferation and survival, stemness, inflammation and immune responses. Aberrant STAT3 activation has been identified as a key driver of tumorigenesis in many types of cancers, including MM. Herein, we summarize the current evidence for the role of STAT3 in affecting cancer hallmark traits by: (1) sustaining MM cell survival and proliferation, (2) regulating tumor microenvironment, (3) inducing immunosuppression. We also provide an update of different strategies for targeting STAT3 in MM with special emphasis on JAK inhibitors that are currently undergoing clinical trials. Finally, we discuss the challenges and future direction of understanding STAT3 signaling in MM biology and the clinical development of STAT3 inhibitors.

Keywords: JAK inhibitor; hallmarks of cancer; multiple myeloma; signal transducer and activator of transcription 3 (STAT3); targeted therapy.

Figure 1

Venn diagrams of genes upregulated in MM cell lines after additional IL-6 stimulation. The MM-STAT3 signature contains 15 upregulated genes shared by studies of Brocke-Heidrich K, et al. (B-H.K., ref. [21]) and Tsuyama N (T.N., ref. [22]).

Figure 2

STAT3 regulates the biological hallmarks and enabling characteristics of multiple myeloma. The key mechanisms of action undertaken by STAT3 in facilitating the hallmarks: (1) sustaining MM cell survival and proliferation; (2) regulating tumor microenvironment (bone marrow niche); (3) inducing immunosuppression, and characteristic pathways and essential genes are listed. Genes or pathways in black font represent overexpression or activation, while gene and cell type and function with down arrows in blue font denote decreased expression, or number or function.