Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia

Autor: Prachi Jani, Asher Chanan-Khan, Kirtipal Bhatia, Sikander Ailawadhi, Michael G. Heckman, Sharoon Akhtar, Salman Ahmed, Fabio Malavasi, Eduardo N. Chini, Aarushi Sharma, Aneel Paulus, Victoria R. Alegria, Sonikpreet Aulakh, Marie V. Coignet, Taimur Sher, Alak Manna, Zahara Meghji
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Chronic lymphocytic leukemia
Receptors
Antigen
B-Cell
Syk
Antineoplastic Agents
Apoptosis
CD38
Article
Mice
03 medical and health sciences
chemistry.chemical_compound
Antineoplastic Agents
Immunological
0302 clinical medicine
Piperidines
immune system diseases
LYN
Cell Line
Tumor
hemic and lymphatic diseases
medicine
Animals
Humans
Bruton's tyrosine kinase
Protein Kinase Inhibitors
Membrane Glycoproteins
biology
business.industry
Adenine
Antibodies
Monoclonal
Daratumumab
Drug Synergism
medicine.disease
ADP-ribosyl Cyclase 1
Leukemia
Lymphocytic
Chronic
B-Cell
Xenograft Model Antitumor Assays
Disease Models
Animal
Leukemia
Pyrimidines
030104 developmental biology
Oncology
chemistry
Ibrutinib
biology.protein
Cancer research
Pyrazoles
business
030215 immunology
Zdroj: Clinical Cancer Research. 25:3974-3985
ISSN: 1557-3265
1078-0432
DOI: 10.1158/1078-0432.ccr-18-3412
Popis: Purpose: CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied. Experimental Design: We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT. Results: In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model. Conclusions: Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.
Databáze: OpenAIRE
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