Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma

Abstract

Targeting the B-cell receptor and phosphatidylinositol 3-kinase/mTOR signaling pathways has shown meaningful, but incomplete, antitumor activity in lymphoma. Glycogen synthase kinase 3 (GSK3) α and β are 2 homologous and functionally overlapping serine/threonine kinases that phosphorylate multiple protein substrates in several key signaling pathways. To date, no agent targeting GSK3 has been approved for lymphoma therapy. We show that lymphoma cells abundantly express GSK3α and GSK3β compared with normal B and T lymphocytes at the messenger RNA and protein levels. Utilizing a new GSK3 inhibitor 9-ING-41 and by genetic deletion of GSK3α and GSK3β genes using CRISPR/CAS9 knockout, GSK3 was demonstrated to be functionally important to lymphoma cell growth and proliferation. GSK3β binds to centrosomes and microtubules, and lymphoma cells treated with 9-ING-41 become arrested in mitotic prophase, supporting the notion that GSK3β is necessary for the progression of mitosis. By analyzing recently published RNA sequencing data on 234 diffuse large B-cell lymphoma patients, we found that higher expression of GSK3α or GSK3β correlates well with shorter overall survival. These data provide rationale for testing GSK3 inhibitors in lymphoma patient trials.

The role of metabolic checkpoint regulators in B cell survival and transformation

“…80 Moreover, increased GSK3 expression in B cell lymphoma patients correlates with reduced overall survival arguing for a tumor promoter role of GSK3. 80 Since GSK3 has many different target molecules and affects a plethora of biological processes, it is possible that the signaling context of the given cell determines the outcome of GSK3 inhibition. A model that would help predict under which conditions GSK3 inhibition induces cell death rather than boosting metabolic activity is crucial in order to be able to use GSK3 inhibitors to treat lymphoma patients.…”

New responsibilities for aged kinases in B‐lymphomas

“…On the other hand, the role of GSK3 could also be of promoting lymphoma cell growth, as shown recently by Wu et al In this work, GSK3 has been proven to be a suitable therapeutic target in NHL. The authors demonstrated that GSK3 is overexpressed in a panel of lymphoma cell lines as compared with normal lymphocytes and that its inhibition with the compound 9‐ING‐41 is associated to lymphoma cell growth arrest . As a further confirmation, none but one GSK3‐null clones could be grown after CRISP‐CAS deletion of the GSK3α and GSK3β genes in lymphoma cell lines, indicating that this kinase is essential for most NHL cell lines tested.…”

“…Interestingly, GSK3 was found to act as a propeller of the cell cycle, in particular mitosis at the prophase stage, by localizing at the centrosome and mitotic spindles. The antiproliferative effects of GSK3 inhibition were confirmed in primary lymphoma cells from patients in vitro and in vivo (Figure B, left) . Inhibition of GSK3 has also been proposed as a therapeutic modality to enhance Myc‐driven apoptosis of chemo‐resistant lymphoma cells .…”

The Role of GSK-3 in Cancer Immunotherapy: GSK-3 Inhibitors as a New Frontier in Cancer Treatment

“…9-ING-41 is an ATP-competitive inhibitor of both GSK-3α and GSK-β isoforms that has been reported to have significant anticancer activity in in vitro and in vivo studies. It has been tested both as a single agent and in combination with standard cytotoxic chemotherapies and novel target-specific agents in a range of solid tumors, such as neuroblastoma [42], pancreatic [43], glioblastoma [35], and bladder [44] cancers, as well as in hematological malignancies, such as lymphoma [45,46].…”