Kinase inhibitors as potential agents in the treatment of multiple myeloma

Abstract

Recent years have witnessed a dramatic increase in the number of therapeutic options available for the treatment of multiple myeloma (MM) - from immunomodulating agents to proteasome inhibitors to histone deacetylase (HDAC) inhibitors and, most recently, monoclonal antibodies. Used in conjunction with autologous hematopoietic stem cell transplantation, these modalities have nearly doubled the disease's five-year survival rate over the last three decades to about 50%. In spite of these advances, MM still is considered incurable as resistance and relapse are common. While small molecule protein kinase inhibitors have made inroads in the therapy of a number of cancers, to date their application to MM has been less than successful. Focusing on MM, this review examines the roles played by a number of kinases in driving the malignant state and the rationale for target development in the design of a number of kinase inhibitors that have demonstrated anti-myeloma activity in both in vitro and in vivo xenograph models, as well as those that have entered clinical trials. Among the targets and their inhibitors examined are receptor and non-receptor tyrosine kinases, cell cycle control kinases, the PI3K/AKT/mTOR pathway kinases, protein kinase C, mitogen-activated protein kinase, glycogen synthase kinase, casein kinase, integrin-linked kinase, sphingosine kinase, and kinases involved in the unfolded protein response.

Oscillating expression of interleukin-16 in multiple myeloma is associated with proliferation, clonogenic growth, and PI3K/NFKB/MAPK activation

“…Based on these initial data we hypothesize that even though JUN and FOS are highly expressed immediately after IL-16 knockdown, IL-16 loss does not lead to their sustained upregulation. We are currently exploring in more detail the downstream elements of IL-16 signaling in order to elucidate the mechanism by which secreted IL-16 affects MAPK and PI3K pathways MM, which have previously been shown to play an important role in in the etiology and maintenance of MM [ 38 – 42 ], rendering them promising therapeutic targets [ 43 ]. Out of all our analyses on the effects of stable IL-16 knockdown on MM cells, the most important observations were the consequences IL-16 withdrawal had on the clonogenic subpopulation within the bulk of tumor cells.…”

The Multiple Myeloma Drug Pipeline—2018: A Review of Small Molecules and Their Therapeutic Targets

“…During the past 2 decades, kinase-activated signaling pathways have been of substantial interest as targets for discovery of new therapeutic classes to treat several cancers, including MM. 108 However, although some small molecule kinase blockers, especially oral tyrosine kinase inhibitors, such as imatinib, dasatinib, nilotinib, and ibrutinib, have had a major effect on the treatment of some hematologic malignancies, other tyrosine kinase inhibitors such as linsitinib, masitinib, cabozantinib, tivantinib, nintedanib, pazopanib, sorafenib, and vatalanib thus far have shown little promise in myeloma-based trials.…”

“…The results of studies with inhibitors of BTK and other kinases (Table 6) might yet prove favorable to MM as innovative molecular design strategies, such as blockade of critical upstream kinase-activating proteineprotein interactions, are instituted in the kinase inhibitor field. 108…”

Endothelial tip cell formation induced by chronic lymphocytic leukemia plasma (JAK2 positivity amplified this effect)

“…In addition, JAK2/STAT3 Data are presented as % mean ± SD signaling pathway was found to be linked with angiogenesis [17]. JAK2 inhibition, therefore, was introduced as a new pharmacological approach to CLL treatment [18,19]. The above data may indicate that CLL plasma as a potential source of VEGF influences on tip cell production resulting in exaggerated angiogenesis activity in CLL [12,20].…”