Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review.

Julian Matthias Metzler,Laurin Burla,Daniel Fink,Patrick Imesch

doi:10.3390/ijms21114154

Julian Matthias Metzler, Laurin Burla + Show 2 more

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https://doi.org/10.3390/ijms21114154

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Abstract

Ibrutinib is an orally available, small-molecule tyrosine kinase inhibitor. Its main purpose is to inhibit Bruton’s tyrosine kinase (BTK), an enzyme that is crucial in B cell development. It is FDA approved for the treatment of certain hematological malignancies. Several promising off-target drug effects have led to multiple, mostly preclinical investigations regarding its use in solid tumors. Unfortunately, data on its effectiveness in gynecological malignancies are limited, and (systematic) reviews are missing. The objective of this review was to summarize the existing literature and to analyze the evidence of ibrutinib as a treatment option in gynecological malignancies, including breast cancer. Studies were identified in MEDLINE and EMBASE using a defined search strategy, and preclinical or clinical research projects investigating ibrutinib in connection with these malignancies were considered eligible for inclusion. Our findings showed that preclinical studies generally confirm ibrutinib’s efficacy in cell lines and animal models of ovarian, breast, and endometrial cancer. Ibrutinib exerts multiple antineoplastic effects, such as on-target BTK inhibition, off-target kinase inhibition, and immunomodulation by interference with myeloid-derived suppressor cells (MDSCs), programmed death-ligand 1 (PD-L1), and T cell response. These mechanisms were elaborated and discussed in the context of the evidence available. Further research is needed in order to transfer the preclinical results to a broader clinical appliance.

Highlights

This publication offered a systematic review of ibrutinib’s current use in gynecological malignancies
After a conceptual and terminological introduction to the drug and the diseases, genes, and proteins covered (I); we reviewed the existing literature on ibrutinib’s use in gynecological malignancies, including breast cancer (II); we analyzed the results and discussed ibrutinib’s multiple mechanisms of action in the context of the literature available (III)
Bruton’s tyrosine kinase (BTK) is a member of the TEC-family kinases (TEC, BTK, BMX, ITK, RLK), a group of non-receptor kinases that modulate intracellular signaling in B- and T-cells and affect cell proliferation, survival, and differentiation in various cell types [4]

Summary

Introduction

This publication offered a systematic review of ibrutinib’s current use in gynecological malignancies. Ibrutinib blocks BTK by forming covalent bonds with cysteine 481 near the ATP binding pocket of the enzyme, resulting in an irreversible inactivation and suppression of downstream effectors [2,4]. In this setting, ibrutinib is FDA approved for the treatment of adult patients with hematological diseases, such as mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom’s macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic graft versus host disease (cGVHD) [5]

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