Clinical cancer research, 2017-10, Vol.23 (19), p.5814-5823
2017
Details
- Autor(en) / Beteiligte
- Titel
- Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model
- Ist Teil von
- Clinical cancer research, 2017-10, Vol.23 (19), p.5814-5823
- Ort / Verlag
- United States: American Association for Cancer Research Inc
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- Targeting the B-cell receptor (BCR) pathway with inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon, and drug resistance with single-agent therapy can occur. studies support the effectiveness of combing PI3Kδ and BTK inhibitors. As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3Kδ inhibitor ACP-319 We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL. We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice. Although single-agent therapy improved survival compared with control mice by a few days, combination therapy extended survival by over 2 weeks compared with either single agent. The combination reduced tumor proliferation, NF-κB signaling, and expression of BCL-xL and MCL-1 more potently than single-agent therapy. The combination of acalabrutinib and ACP-319 was superior to single-agent treatment in a murine CLL model, warranting further investigation of this combination in clinical studies. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-0432eISSN: 1557-3265DOI: 10.1158/1078-0432.CCR-17-0650Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5626587
- Format
- –
- Schlagworte
- Adenosine - pharmacology, Agammaglobulinaemia Tyrosine Kinase, Animal models, Animals, Apoptosis - drug effects, B-cell receptor, B-Lymphocytes - drug effects, Bcl-x protein, Benzamides - administration & dosage, Bruton's tyrosine kinase, Cancer, Cell Line, Tumor, Cell Proliferation - drug effects, Cell survival, Chronic lymphatic leukemia, Class Ia Phosphatidylinositol 3-Kinase - antagonists & inhibitors, Class Ia Phosphatidylinositol 3-Kinase - genetics, Disease Models, Animal, Drug resistance, Drug Resistance, Neoplasm - genetics, Experimental design, Gene Expression Regulation, Neoplastic - drug effects, Humans, Inhibitors, Leukemia, Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell - genetics, Leukemia, Lymphocytic, Chronic, B-Cell - pathology, Lymphatic leukemia, Lymphocytes B, Mcl-1 protein, Mice, Neoplasm Proteins - genetics, NF-κB protein, Peripheral blood, Protein Kinase Inhibitors - administration & dosage, Protein-tyrosine kinase, Protein-Tyrosine Kinases - antagonists & inhibitors, Protein-Tyrosine Kinases - genetics, Pyrazines - administration & dosage, Quinolines - pharmacology, Signaling, Spleen, Survival, Therapy, Tumor Microenvironment - drug effects, Tyrosine