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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]
ND-2158 (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]
PU-H71 (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 [258]
TP-0903 (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]
B-PAC-1 (pro-caspase activating compound) CLL B cells from patients on ibrutinib therapy B-PAC activates caspases dimers Induced cytotoxicity in leukemic cells [259]
Carfilzomib (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]
Selinexor (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 [243]
ABT-199 (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]
ABT-199 (BCL-2 antagonist) MCL CCMCL1 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]
CpG (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]
BAY80–6946 (PIK3 inhibitor) INK128 (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]
Idelalisib (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 [267]1
Idelalisib (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