Ibrutinib in the Treatment of Solid Tumors: Current State of Knowledge and Future Directions

Abstract

Bruton’s Tyrosine Kinase (BTK) is considered crucial in the activation and survival of both physiological and malignant B-cells. In recent years, ibrutinib, an oral BTK inhibitor, became a breakthrough therapy for hematological malignancies, such as chronic lymphocytic. However, ibrutinib’s feasibility might not end there. Several other kinases with established involvement with solid malignancies (i.e., EGFR, HER2) have been found to be inhibited by this agent. Recent discoveries indicate that BTK is a potential anti-solid tumor therapy target. Consequently, ibrutinib, a BTK-inhibitor, has been studied as a therapeutic option in solid malignancies. While most preclinical studies indicate ibrutinib to be an effective therapeutic option in some specific indications, such as NSCLC and breast cancer, clinical trials contradict these observations. Nevertheless, while ibrutinib failed as a monotherapy, it might become an interesting part of a multidrug regime: not only has a synergism between ibrutinib and other compounds, such as trametinib or dactolisib, been observed in vitro, but this BTK inhibitor has also been established as a radio- and chemosensitizer. This review aims to describe the milestones in translating BTK inhibitors to solid tumors in order to understand the future potential of this agent better.

90Y-Labeled Gold Nanoparticle Depot (NPD) Combined with Anti-PD-L1 Antibodies Strongly Inhibits the Growth of 4T1 Tumors in Immunocompetent Mice and Induces an Abscopal Effect on a Distant Non-Irradiated Tumor

“…Ibrutinib inhibits B-cell signaling and is used to treat B-cell malignancies but has also shown activity toward solid tumors due to its ability to inhibit multiple kinases. 32 Furthermore, since the primary tumor in our study was strongly growth-inhibited by the NPD incorporating 90 Y-AuNPs, this made it difficult to detect enhancement in effectiveness when combined with anti-PD-L1 antibodies. The reason for the modest primary tumor growth inhibition by NPD incorporating unlabeled AuNPs is not known, but AuNPs have been to inhibit the growth of ovarian cancer tumors in mice by inhibiting mitogen-activated protein kinase signaling.…”

“…similarly found that treatment of 4T1 tumors in Balb/c mice with anti-PD-L1 antibodies alone was ineffective, but combining checkpoint immunotherapy with the Bruton’s tyrosine kinase inhibitor, ibrutinib , improved tumor response. Ibrutinib inhibits B-cell signaling and is used to treat B-cell malignancies but has also shown activity toward solid tumors due to its ability to inhibit multiple kinases . Furthermore, since the primary tumor in our study was strongly growth-inhibited by the NPD incorporating 90 Y-AuNPs, this made it difficult to detect enhancement in effectiveness when combined with anti-PD-L1 antibodies.…”

Bruton’s Tyrosine Kinase Inhibitor Zanubrutinib Effectively Modulates Cancer Resistance by Inhibiting Anthracycline Metabolism and Efflux

“…Finally, the role of ABC transporters in cancer responses to ANT-containing chemotherapy has been suggested in DLBCL [ 70 ], MCL [ 71 ], and Burkitt lymphoma [ 72 ]. In addition to the primary indication of BTK inhibitors in CLL and lymphomas, their efficacy has recently been demonstrated in AML and solid tumours [ 73 , 74 , 75 , 76 ]. Rushworth et al (2014) discovered that BTK is phosphorylated (p-BTK), and is thus constitutively active in the majority of samples obtained from patients with AML.…”

Chalcone Scaffold: A masterpiece for medicinal chemistry recent biological insights

“…Additionally, traditional chemotherapy may result in more mutations, which could result in the growth of additional cancers or the progression of treatment resistance in the initial tumor [56]. On the other hand, targeted therapies are created to block particular biochemical pathways in cancer cells that result in tumor cell death without harming DNA [57]. Enzymes called protein kinases catalyze the transfer of a phosphate group to a specific amino acid in a protein, altering the protein's functionality [58].…”