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Table 2 Overview of Ibrutinib in combination therapies

From: Role of Bruton’s tyrosine kinase in B cells and malignancies

Combination Disease Model Rationale Effect Reference
γ-secretase inhibitors
(crucial protease in Notch signaling)
CLL CLL patient cells NOTCH1 signaling is related to resistance to therapy in B-CLL. Combination therapy showed enhanced cytotoxicity and reduced CXCR4 expression and functions (response to SDF-1α) [255]
Histone Deacetylase (HDACs) Inhibitor CLL - MCL cell line
- mice engrafted with TCL-1 splenocytes
HDACs increase transcription of miRNA that repress BTK HDAC induced increase in target miRNA and a decrease in BTK RNA; combination exhibited higher cytotoxicity than either drug alone; reduction of p-BTK and total BTK protein. [69]
Anti-CD19 CAR T Cells (CART19) MCL MCL
Xenograph model
Efficient B cell depletion Long-term remission in 80–100% of mice (treated with CART19 only: 0–20% of mice) [245]
Ethacridine (Poly(ADP-ribose) glycohydrolase inhibitor) AML SCID mice injected s.c. with OCI-AML2 cells Result of a drug screening High decrease of OCI-AML2 cell growth (more than with either drug alone). Suggested mechanism: increased intracellular ROS production in cells treated with combination. [256]
(IRAK4 inhibitor)
ABC-DLBCL - ABC-DLBCL cell lines OCI-Ly10 and TMD8
- OCI-Ly10 xenografts
MYD88-IRAK4 signaling is important for ABC- DLBCL viability Combination was more effective than ND-2158 alone in inhibiting IKK activity, enhancing apoptosis, and blocking tumor growth in mice. [257]
(Binds to tumor enhanced HSP90 complexes)
ABC-DLBCL DLBCL cell lines (HBL-1 and TMD8) teHSP90 complexes are associated with tumor survival. PU-H71 disrupts teHSPP90 (but not house-keeping fractions associated with HSP90).
Synergistic effect, with ~ 95% tumor growth inhibition; decreased NF-kB activity
(AXL inhibitor)
CLL Patient CLL cells prior to or after ibrutinib therapy AXL contributes to oncogenic survival in CLL. TP-093 disrupts the activity of AXL; Induction of cell-death in a dose-dependent fashion [259]
(pro-caspase activating compound)
CLL B cells from patients on ibrutinib therapy B-PAC activates caspases dimers Induced cytotoxicity in leukemic cells [259]
(proteasome inhibitor)
CLL Primary CLL patient samples MEC-1 and MEC2 cell lines Upregulation of pro-apoptotic transcription factor CHOP Combination showed an additive cytotoxic effect; Carfilzomib induced a pro-apoptotic response involving Noxa, MCL-1, Bax, and Bak and intrinsic and extrinsic caspase pathways [260]
(Exportin inhibitor)
CLL Primary CLL patient samples Selinexor disrupts BCR signaling via BTK depletion Combination showed synergistic cytoxicity. Selinexor overcomes resistance to Ibrutinib (also in patient cells with C481S mutation) [261]
Anti-PDL1 antibody
(Negative regulator of T cell function)
B cell lymphoma (A20) - BALB/c mice inoculated with A20 B cells
- A20 B cells are resistant to Ibrutinib
Blocking immune checkpoints can enhance the anti-tumor response Anti-PDL-1 treatment alone delayed tumor growth and slightly increased mouse survival
Combination with anti-PDL-1 cured ~ 50% of the mice, delayed tumor growth and prolonged survival in the remaining mice, and increased IFN-γ producing T-cells
(BCL-2 antagonist)
CLL Ex vivo samples from CLL patients on ibrutinib CLL samples show enhanced BCL-2 expression Ibrutinib enhances ABT-199 cytotoxicity, both in unstimulated and in αIgM-stimulated CLL cells from. ABT-199 action correlated with a decline in expression of anti-apoptotic MCL-1 [262]
(BCL-2 antagonist)
MCL cell line
MCL cells show enhanced BCL-2 expression Combination results in decrease of p-BTK and p-AKT. Downregulation of both BCL2 and MCL1. ABT-199 and Ibrutinib target non-overlapping pathway s [263]
Bortezomib (proteosome inhibitor) and lenalidomide chemotherapy MM Cells from MM patients and MM cell lines Blocking BTK to downregulate NF-kB activation and cell survival Ibrutinib increased the cytotoxicity of bortezomib and lenalidomide in both patient cells and cell lines [264]
(TLR9 ligand)
B-cell lymphoma Murine pre-B cell (H11) and B cell lymphoma lines (BL3750, A20) CpG activates APCs and thereby induces T cell activation Combination of ibrutinib and intratumoral CpG resulted in tumor regression and resistance, whereby IFNy-producing CD4 and CD8 T are essential [265]
Sudemycin D1 (spliceosome modulator) CLL Primary CLL cells (from SF3B1-unmutated and mutated cases) SF3B1 is frequently mutated in CLL, and correlates with aggressiveness Combination results in enhanced apoptosis of M-CLL and U-CLL. Effect is related to IBTK splicing. Sudemycin D1 downregulates anti-apoptotic MCL-1 through alternative splicing [266]
(PIK3 inhibitor)
(mTOR inhibitor)
PCNSL - Xenograft model from CD79B-mutant biopsies CARD11 domain mutations increase the activity of the PIK3-mTOR axis In cell lines, cell death was induced with both combinations of drugs [177]
(PI3K inhibitor)
DLBCL - Cell lines.
- Mouse TMD8 xenograft model
PI3K is upstream regulator of NF-кB pathway. Cell lines: combination induced 50% apoptosis and inhibited signaling (more than either drug individually).
Mouse xenograft: Significant tumor regression
(PI3K inhibitor)
MCL MCL cell lines A more robust blockage of BCR signaling Inhibition of BCR-stimulated integrin- mediated adhesion; stronger inhibition of adhesion compared to each drug alone [146]1
  1. 1In this study, also ONO/GS-4059, the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 and the AKT inhibitor MK-2206 were investigated
  2. CLL Chronic Lymphocytic leukemia, MCL Mantle cell lymphoma, AML Acute Myeloid Leukemia, ABC-DLBCL Activated B-cell Diffuse large B cell Lymphoma, MM Multiple Myeloma, PCNSL Primary central nervous system lymphoma