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.
Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6±10.4months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the "watch-and-wait" phase of management.
B cell receptor (BCR)-signaling inhibitors such as Ibrutinib and Idelalisib do not cure CLL, suggesting the importance of other pathways.1 Cytokines are also important in CLL biology and mediate transcription of oncogenic genes such as miR-17 by activating signal transducer and activator of transcription (STAT) proteins including STAT5A/B and STAT3 through Janus kinases (JAKs).2–4 We hypothesized that Ruxolitinib, a selective JAK1/2 inhibitor licensed for myelofibrosis,5 might have unrecognized activity in CLL and designed a single center phase II trial to evaluate it in patients considered unfit for FCR on the basis of age and comorbidities.6 The demonstrated safety of Ruxolitinib in myelofibrosis was felt to make it ethical to use as first-line therapy for elderly CLL patients. The primary endpoint was overall response rate (ORR) assessed after 7 treatment cycles.7 Secondary endpoints were safety and tolerability.7 The study was approved by the Sunnybrook REB and Health Canada and registered with ClinicalTrials.gov, {type:clinical-trial,attrs:{text:NCT02015208,term_id:NCT02015208}}NCT02015208.
