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Open AccessReview

Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell Lymphomas

1
Department of Hematopathology, MD Anderson Cancer Center, Houston, TX 77030, USA
2
Department of Internal Medicine, the Ohio State University, Columbus, OH 43210, USA
3
Department of Medical Oncology & Hematology, All India Institute of Medical Sciences, Rishikesh 249203, India
4
Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh 249203, India
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(5), 1328; https://doi.org/10.3390/cancers12051328
Received: 6 May 2020 / Revised: 17 May 2020 / Accepted: 19 May 2020 / Published: 22 May 2020
Chronic activation of B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) is largely considered to be one of the primary mechanisms driving disease progression in B–Cell lymphomas. Although the BTK-targeting agent ibrutinib has shown promising clinical responses, the presence of primary or acquired resistance is common and often leads to dismal clinical outcomes. Resistance to ibrutinib therapy can be mediated through genetic mutations, up-regulation of alternative survival pathways, or other unknown factors that are not targeted by ibrutinib therapy. Understanding the key determinants, including tumor heterogeneity and rewiring of the molecular networks during disease progression and therapy, will assist exploration of alternative therapeutic strategies. Towards the goal of overcoming ibrutinib resistance, multiple alternative therapeutic agents, including second- and third-generation BTK inhibitors and immunomodulatory drugs, have been discovered and tested in both pre-clinical and clinical settings. Although these agents have shown high response rates alone or in combination with ibrutinib in ibrutinib-treated relapsed/refractory(R/R) lymphoma patients, overall clinical outcomes have not been satisfactory due to drug-associated toxicities and incomplete remission. In this review, we discuss the mechanisms of ibrutinib resistance development in B-cell lymphoma including complexities associated with genomic alterations, non-genetic acquired resistance, cancer stem cells, and the tumor microenvironment. Furthermore, we focus our discussion on more comprehensive views of recent developments in therapeutic strategies to overcome ibrutinib resistance, including novel BTK inhibitors, clinical therapeutic agents, proteolysis-targeting chimeras and immunotherapy regimens. View Full-Text
Keywords: ibrutinib; acquired resistance; genetic alterations; tumor microenvironment; BTK-PROTAC; CAR T-cells ibrutinib; acquired resistance; genetic alterations; tumor microenvironment; BTK-PROTAC; CAR T-cells
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George, B.; Mullick Chowdhury, S.; Hart, A.; Sircar, A.; Singh, S.K.; Nath, U.K.; Mamgain, M.; Singhal, N.K.; Sehgal, L.; Jain, N. Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell Lymphomas. Cancers 2020, 12, 1328.

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