Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

Abstract

Bruton tyrosine kinase (Btk) has a welldefined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis.

Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

“…Importantly, OCs, also of monocyte-derived lineage, are highly activated in the BM microenvironment to promote proliferation and survival of MM cells. 33 In this study, we further identify an Human galectin-9 concentration (ng/mL) immunosuppressive role of OCs in the MM BM microenvironment via 3 mechanisms (supplemental Figure 3): (1) induction of T-cell apoptosis by upregulating immune checkpoint proteins PD-L1, Galectin-9, HVEM, and CD200; (2) induction of IDO and CD38, which regulate T-cell metabolism and function; and (3) production of cytokines, especially APRIL, which further induces PD-L1 in MM cells. Importantly, therapeutic anti-CD38 mAb partially overcame the immunosuppressive effect of OCs associated with decreased HVEM and IDO, thereby restoring the cytotoxic function of T cells.…”

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

“…As BTK is emerging as an important regulator of downstream survival pathways in MM, 17,23 and further to our observations of enhanced BTK activity and expression in bortezomib-resistant MM cells (Fig. 2), we investigated the functional effect of combined pharmacological BTK inhibition and bortezomib treatment in bortezomib-na€ ıve and bortezomib-resistant MM cell lines and primary human MM samples.…”

“…21 Conversely, however, bortezomib also enhances 'constitutive' levels of NF-kB through activation of IKKb, ultimately leading to NF-kB nuclear translocation and the transcription of multiple NF-kB-induced genes, including Bruton's tyrosine kinase (BTK). 22 BTK, a non-receptor tyrosine kinase, is now known to be of key importance to a number of haematological malignancies, including MM, 23 chronic lymphocytic leukemia (CLL) 24 and acute myeloid leukemia (AML). 25 The potential feedback mechanism between NF-kB and BTK signaling, whereby BTK also lies upstream of several NF-kB inducible signaling pathways, 26,27 provides a rationale for investigation of combined NF-kB and BTK inhibition in MM.…”

“…17,23 Specifically, we have shown that the irreversible BTK inhibitor ibrutinib can enhance the action of bortezomib via repression of the NF-kB survival pathway in primary tissue, e.g., bone marrow-derived MM cells from treatment-na€ ıve patients. 17 Despite these findings, however, early phase II clinical trial data for ibrutinib monotherapy in MM have so far proved disappointing, 28 while the study of ibrutinib efficacy in patients with relapsed of refractory MM is currently recruiting (ClinicalTrials.gov Identifier:NCT01478581).…”

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

“…[1][2][3] The introduction of novel agents, thalidomide, lenalidomide, bortezomib, but also the availability of various others, such as 3rd-generation immunomodulatory drugs (IMiDs; pomalidomide), novel proteasome inhibitors, including carfilzomib, ixazomib and oprozomib, antibodies, such as elotuzumab (target: CS1), daratumumab and SAR650984 (CD38), siltuximab (IL-6), tabalumab (BAFF), denosumab (RANKL), romosozumab (sclerostin), Bruton tyrosine kinase, heat shock protein inhibitors and other innovative phase I/II agents have changed or will alter the therapeutic scenario in several ways. [4][5][6][7] Moreover, cereblon (CRBN) has been identified as a possible biomarker for the assessment of clinical efficacy of IMiDs, although this is still a subject of controversy and CRBN testing needs to be standardized. 8,9 The predictive role of CRBN was assessed in the HOVON/GMMG trial, where higher CRBN expression was associated with better survival and clinical efficacy of thalidomide.…”