Bruton's Tyrosine Kinase Targeting in Multiple Myeloma

Max Von Suskil; Kazi Nasrin Sultana; Weam Othman Elbezanti; Omar S Al-Odat; Robert Chitren; Amit K Tiwari; Kishore B Challagundla; Sandeep Kumar Srivastava; Subash C Jonnalagadda; Tulin Budak-Alpdogan; Manoj K Pandey

doi:10.3390/ijms22115707

Bruton's Tyrosine Kinase Targeting in Multiple Myeloma

Int J Mol Sci. 2021 May 27;22(11):5707. doi: 10.3390/ijms22115707.

Authors

Max Von Suskil^{1

2}, Kazi Nasrin Sultana³, Weam Othman Elbezanti^{1

4}, Omar S Al-Odat^{1

2}, Robert Chitren^{1

2}, Amit K Tiwari^{5

6}, Kishore B Challagundla^{7

8

9}, Sandeep Kumar Srivastava³, Subash C Jonnalagadda², Tulin Budak-Alpdogan⁴, Manoj K Pandey¹

Affiliations

¹ Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA.
² Department of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ 08028, USA.
³ Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India.
⁴ Department of Hematology, MD Anderson Cancer Center at Cooper, Cooper Health University, Camden, NJ 08103, USA.
⁵ Department of Pharmacology and Experimental Therapeutics, The University of Toledo, Toledo, OH 43606, USA.
⁶ Department of Cancer Biology, College of Medicine & Life Sciences, The University of Toledo, Toledo, OH 43614, USA.
⁷ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁸ The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁹ The Children's Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Abstract

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones' hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton's Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones' interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM.

Keywords: Bruton’s Tyrosine Kinase (BTK) inhibitors; drug development; microenvironment; multiple myeloma; resistance.

Publication types

Review

MeSH terms

Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
Agammaglobulinaemia Tyrosine Kinase / chemistry
Agammaglobulinaemia Tyrosine Kinase / metabolism
Biomarkers, Tumor
Bone Marrow / metabolism
Bone Marrow / pathology
Disease Management
Disease Susceptibility
Drug Resistance, Neoplasm
Humans
Molecular Targeted Therapy* / methods
Multiple Myeloma / drug therapy*
Multiple Myeloma / etiology
Multiple Myeloma / metabolism
Multiple Myeloma / pathology
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Signal Transduction
Structure-Activity Relationship
Tumor Microenvironment / drug effects

Substances

Biomarkers, Tumor
Protein Kinase Inhibitors
Agammaglobulinaemia Tyrosine Kinase