Janus and PI3-kinases mediate glucocorticoid resistance in activated chronic leukemia cells

Abstract

Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis. The JAK1/2 inhibitor ruxolitinib blocked STAT3-phosphorylation and partially improved DEX-mediated killing of stimulated CLL cells in vitro but not in CLL patients in vivo. An automated microscopy-based screen of a kinase inhibitor library implicated an additional protective role for the PI3K/AKT/FOXO pathway. Blocking this pathway with the glycolysis inhibitor 2-deoxyglucose (2-DG) or the PI3K-inhibitors idelalisib and buparlisib increased DEX-mediated killing but did not block STAT3-phosphorylation. Combining idelalisib or buparlisib with ruxolitinib greatly increased killing by DEX. These observations suggest that glucocorticoid resistance in CLL cells may be overcome by combining JAK and PI3K inhibitors.

Persistent janus kinase‐signaling in chronic lymphocytic leukemia patients on ibrutinib: Results of a phase I trial

“…However, the utility of this regimen may lie in its ability to enhance therapeutic responses to cytotoxic drugs . Neither ibrutinib, ruxolitinib, nor the combination is cytotoxic to CLL cells in vitro and it is not well‐understood how CLL cells are eliminated by ibrutinib in vivo . Ibrutinib may sensitize CLL cells to cytotoxic stresses in the body by flushing them out of protective microenvironments in part by blocking CXCR4‐signaling .…”

Ibrutinib therapy downregulates AID enzyme and proliferative fractions in chronic lymphocytic leukemia

“…31 PI3K/AKT and JAK1 pathways are important drivers of cell proliferation and cell survival, most notably in cells that are responding to growth-factor-receptor engagement in tumor microenvironments. 65,66 Interestingly, a common activation stimulus of these 2 axes is IL-4, which in synergism with CD40L are responsible to promote B-cell proliferation and activation of CSR to IgG 1 and IgE immunoglobulins. 53,67 The signal transduction used by IL-4 to activate B cells involves tyrosine phosphorylation of the IL-4 receptor and JAK1 and STAT6 proteins.…”

Comparing the value of mono- versus coculture for high-throughput compound screening in hematological malignancies

“…Although JAK inhibitors alone have low inhibitory activity, they could be used in combination with other clinically established drugs to reduce drug resistance in the bone marrow. Currently, JAK inhibitor combinations are being evaluated in clinical trials (Oppermann et al 2016; Spaner et al 2016; Spaner et al 2019).…”