Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review

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.

Targeting Solid Tumors With BTK Inhibitors

“…Furthermore, BTKi ibrutinib inhibited the proliferation of human colorectal cancer cell lines in vitro (Grassilli et al, 2016) and enhanced the chemosensitivity of drug-resistant colorectal cancer cells (Ianzano et al, 2016). Inhibition of BTK also reduced the clonogenicity of cancer stem cells and decreased their resistance to chemotherapy drugs (Metzler et al, 2020). BTKi were shown to synergize with the standard chemotherapy drug 5-fluorouracil against chemotherapy-resistant colorectal cancer cells (Lavitrano et al, 2019).…”

“…Similarly, numerous studies have shown that BTK inhibition causes substantial cytotoxicity to HER2 + breast cancer cells, inhibits their proliferation and clonogenicity, and diminishes their resistance to chemotherapy both in vitro and in vivo (Eifert et al, 2013;Chen et al, 2016;Wang et al, 2016;Metzler et al, 2020;Wen et al, 2020). The results obtained with non-specific BTKi like ibrutinib should be interpreted with due caution because several other kinases, including ERBB2/HER-2 that have ibrutinib-binding cysteine residues in their kinase domains are inhibited by ibrutinib (Berglof et al, 2015).…”

Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets – Beyond B Lymphocytes

“…It is increasingly clear that in addition to their direct effects on B cells, both BTK inhibitors also directly impact the phenotype and function of many other cell subsets of the immune system, which contribute to their high efficacy as well as adverse effects observed in CLL and MCL patients. Interestingly, such immunomodulatory effects of ibrutinib and acalabrutinib are being exploited to treat a variety of other human diseases, including other hematological malignancies, solid tumors, graft-versus-host disease (GVHD), autoimmune disorders, atherothrombosis, allergy and infectious diseases (Zaitseva et al, 2014;Pillinger et al, 2015;Rushworth et al, 2015;Miklos et al, 2017;Molina-Cerrillo et al, 2017;Dispenza et al, 2018;Florence et al, 2018;Mamand et al, 2018;Rip et al, 2018;Allchin et al, 2019;de Porto et al, 2019;Goldmann et al, 2019;O'Riordan et al, 2019;Riccio et al, 2019;Varikuti et al, 2019;Waller et al, 2019;Hu et al, 2020;Lorenzo-Vizcaya et al, 2020;Metzler et al, 2020;Purvis et al, 2020;Shaker et al, 2020;Teusink-Cross et al, 2020;Nadeem et al, 2021;Nicolson et al, 2021;Wen et al, 2021). Most notably, the repositioning therapeutic potential of BTK inhibitors has been demonstrated by recent application of acalabrutinib in the management of severe respiratory syndrome in patients with COVID-19 (Rada et al, 2020;Roschewski et al, 2020;Treon et al, 2020;Benner and Carson, 2021;Fiorcari et al, 2021;McGee et al, 2021).…”

Prognostic And Immunological Implications of BTK Expression In Pan-Cancer

“…Three additional agents targeting BTK have been developed: zanubrutinib (BGB-3111) [17], acalabrutinib (ACP-196) [18], and tirabrutinib (ONO/GS-4059) [19]. In addition to the demonstrated effectiveness of BTK inhibitors in hematological malignancies, several studies have revealed positive therapeutic results in solid tumors [20,21], such as in non-small cell lung cancer (NSCLC) [22], breast cancer [23], as well as pancreas ductal adenocarcinoma (PDAC) [24]. The potential mechanisms of BTK inhibitors in solid tumors may be related to the dual spectrum of activity of these inhibitors on additional binding enzymes (such as the ERBB family) [25] and the importance of BTK in the tumor microenvironment (TME).…”