Ibrutinib-A double-edge sword in cancer and autoimmune disorders

Abstract

Targeted therapies have appeared as new treatment options for several disease types, including cancer and autoimmune disorders. Of several targets, tyrosine kinases (TKs) are among the most promising. Overexpression of TKs provides a target for novel therapeutic agents, including small molecule inhibitors of tyrosine kinases (TKI). Ibrutinib (PCI-32765) is a TKI of Bruton's tyrosine kinase (Btk), a key kinase of the B-cell receptor signaling pathway that plays a significant role in the proliferation, differentiation and survival of B cells. In addition to inhibitory effects, recent studies have shown that ibrutinib has multiple immunomodulatory effects. It binds covalently to IL-2 inducible tyrosine kinase (Itk) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells. This changes the balance of Th1/Th2 cells toward Th1 subset, which are the main immune cells targeting tumor cells. The dual activity of ibrutinib has paid a great attention and several studies are evaluating the anti-tumor and immunomodulatory effects in cancer, autoimmune disorders and infectious diseases. In this article we review the inhibitory and immunomodulatory effects of ibrutinib in B-cell malignancies, autoimmune diseases and infections, as well as the communication between the Ror1 receptor tyrosine kinase and BCR and effects of ibrutinib on this crosstalk.

The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein

“…Currently, the drug is being evaluated for treatment of other diseases, including other malignancies, autoimmune disease, inflammatory diseases, osteoclast-associated bone diseases, and ischemic stroke (21)(22)(23)(24)(25)(26). As is the case for other targeted tumor therapies (27), ibrutinib treatment is characterized, in some cases, by the development of acquired drug resistance (28).…”

Mechanisms of tumor cell resistance to the current targeted-therapy agents

“…However, downregulation of ROR1 or BCR did not induce the same effects, suggesting complementary effects. The data also indicated an intracellular link (PI3K/AKT) between the BCR and ROR1 signaling pathways [139,164].…”

“…Crosstalk between several intracellular signaling pathways is one of the major reasons for acquired resistance to targetedtherapy agents [139]. BCR and receptor tyrosine kinase-like orphan receptor 1 (ROR1) [157][158][159][160][161][162][163] signaling pathway cross-communication is an example that has been recently reported [164].…”

“…Recently, a cysteine-to-serine mutation in BTK (C481S) has been shown that converts ibrutinib covalent binding to reversible binding with the lower effect of ibrutinib [138]. Moreover, two mutations in PLCγ2 (R665W/ arginine to tryptophan substitution at position 665 and L845F/ leucine to phenylalanine substitution at position 845) that are gain-of-function mutations have been described to be involved in ibrutinib resistance in CLL patients [138,139].…”

Application of nanomedicine for crossing the blood–brain barrier: Theranostic opportunities in multiple sclerosis

“…Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of MS that has been induced via immunization with spinal cord homogenates, myelin or specific myelin peptides (Gharibi et al 2015). Despite several attempts to develop treatments for MS, effective drugs with fewer side effects are still needed (Kim et al 2015;Kokhaei et al 2015).…”