Ibrutinib repurposing: from B-cell malignancies to solid tumors

Ibrutinib (Imbruvica ® , also known as PCI-32765) is a first-in-class, irreversible small-molecule inhibitor of Bruton's Tyrosine Kinase (BTK) that binds covalently to cysteine C481 within the ATP-binding pocket. Since BTK is a Tec family non-receptor tyrosine kinase that is specifically required for B-cell antigen receptor (BCR) signaling, ibrutinib was initially developed for the treatment of B-cell malignancies. Currently, it is approved for first-line treatment of chronic lymphocytic leukemia, and for the treatment of mantle-cell lymphoma and Waldenström's macroglobulinemia patients that have received at least one previous therapy. However, BTK is also involved in signaling pathways downstream of many other receptors and its expression is not restricted to B cells. In fact, it is expressed in all hematopoietic lineages with the exception of T lymphocytes. Taking advantage of this aspect of BTK biology, some groups, including ours, have exploited the utility of inhibiting BTK in different cell types other than B cells. In particular, we validated the critical role of BTK for mast cell degranulation in mouse models of pancreatic cancer, namely insulinoma [1] and pancreatic ductal adenocarcinoma (PDAC) [2]. Ibrutinib was effective in both scenarios, leading to vasculature collapse and tumor regression in insulinoma and to a potent and unexpected anti-fibrotic effect in PDAC, where it synergized with standard of care chemotherapy to extend mice survival. This latter observation suggests that the anti-fibrotic activity of ibrutinib could be beneficial also for the treatment of other fibrotic diseases, an aspect that deserves further studies. More recently, Gunderson and colleagues contributed to the understanding of ibrutinib therapeutic impact in PDAC by describing how BTK regulates B-cell and macrophage-mediated T-cell suppression and demonstrating that ibrutinib restores T-cell dependent anti-tumor responses and triggers growth inhibition [3]. These studies combined led to the initiation of a phase 2/3 clinical trial for the use of ibrutinib in combination with nab-paclitaxel and gemcitabine in metastatic PDAC. Importantly, emerging data obtained from various mouse models of cancer suggests that beneficial use of ibrutinib could extend beyond pancreatic cancer to other solid tumors. For example, myeloid-derived suppressor cells (MDSCs) express BTK and are present in the stroma of many different tumors, causing immunosuppression and evasion of anti-tumor immune responses. Consistently, treatment of breast cancer and melanoma mouse models with ibrutinib reduced the number of MDSCs in the spleen and the tumor, and combination therapy with anti-PD-L1 resulted in reduced mammary tumor growth [4]. Moreover, synergy of ibrutinib with …