pci-32765 and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Inhibitors of B-cell receptor (BCR) and pre-BCR signaling were successfully introduced into patient care for various subtypes of mature B-cell lymphoma (e.g., ibrutinib, idelalisib). Acute lymphoblastic leukemia (ALL) typically originates from pre-B cells that critically depend on survival signals emanating from a functional pre-BCR. However, whether patients with ALL benefit from treatment with (pre-) BCR inhibitors has not been explored. Recent data suggest that the pre-BCR functions as tumor suppressor in the majority of cases of human ALL. However, a distinct subset of human ALL is selectively sensitive to pre-BCR antagonists.

Topics: Adenine; DNA-Binding Proteins; Humans; Molecular Targeted Therapy; Piperidines; Pre-B Cell Receptors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; Proto-Oncogene Proteins c-bcl-6; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; STAT5 Transcription Factor

Asparaginase (ASNase) therapy has been a mainstay of acute lymphoblastic leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we used a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's tyrosine kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc-mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient-derived xenografts, regardless of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL. This trial was registered at www.clinicaltrials.gov as # NCT02884453.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Amino Acids; Animals; Antineoplastic Agents; Apoptosis; Asparaginase; Cell Line, Tumor; Humans; Mice; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Signal Transduction

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Bispecific; Antineoplastic Agents, Immunological; Cell Line, Tumor; Humans; Immunity, Cellular; Neoplasm Proteins; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; T-Lymphocytes

The current study mainly aims to evaluate the effects of ibrutinib on endoplasmic reticulum stress (ERS)-induced apoptosis in Reh cells, which may shed light on the treatment of acute lymphoblastic leukemia (ALL) among children. In line with previous studies, our data show that ibrutinib significantly suppressed Reh cell viability in a time- and dose-dependent manner. We further evaluated the role of ibrutinib on Reh cell colony formation and apoptosis. Ibrutinib inhibited clonogenic capacity and induced Reh cell apoptosis, suggesting an anti-tumor effects of ibrutinib in the progression of ALL. Further study showed that ibrutinib treatment increased ERS-related protein expression, including Bip, ATF4 and CHOP, suggesting the induction of ER-stress in Reh cells. More importantly, once ER-stress was suppressed by tauroursodeoxycholic acid (TUDCA), an ER-stress inhibitor, the upregulation of Bip, ATF4, CHOP, cleaved-caspase3 and cleaved-PARP after ibrutinib treatment was partially reversed, suggesting that induction of ALL cell apoptosis by ibrutinib was partially attributed to activation of ER stress. In summary, we showed novel data that ER-stress induced cell apoptosis plays a key role in the therapeutic effects of ibrutinib on ALL cell malignancies.

Topics: Activating Transcription Factor 4; Adenine; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Survival; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Humans; Piperidines; Poly (ADP-Ribose) Polymerase-1; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Taurochenodeoxycholic Acid; Transcription Factor CHOP

A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17μM and 6.69μM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree. In a word, compound 7b is a promising BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Flow Cytometry; Humans; Molecular Dynamics Simulation; Molecular Structure; Organophosphorus Compounds; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Structure-Activity Relationship

To explore the effect of Ibrutinib on the chemoresistance mediated by SDF-1α/CXCR4 axis in ALL cells.. Flow cytometry was used to detect the apoptosis of cell line and expression of surface membrane CXCR4, Western blot was used to determine the expression level of CXCR4, ERK and Bcl-xL proteins, qPCR was used to assay the mRNA level of CXCR4.. Ibrutinib enhanced the apoptosis induced by adriamycin(ADR) (17.100±4.3% to 28.133±3.16%); Ibrutinib inhibited the phosphorylation of CXCR4 induced by SDF-1α and with concentration- and time- dependent manner (r

Topics: Adenine; Chemokine CXCL12; Drug Resistance, Neoplasm; Humans; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrazoles; Pyrimidines; Receptors, CXCR4