The up-regulation of the enzyme glutaminase (GLS), which plays a critical role in cancer cell metabolism, is a common feature in Philadelphia-negative (Ph-) and JAK2-V617F-driven myeloproliferative neoplasms (MPNs), according to a study presented at the 2023 American Society of Clinical Oncology Annual Meeting.
Almost all MPNs are driven by somatic mutations in either JAK2, CALR, or MPL. While these mutations lead to activation of JAK/STAT signaling, lead researcher Michele Ciboddo and colleagues noted that “JAK inhibitors are not curative and fail to alter disease progression and display unwanted side effects. Allogeneic stem cell transplantation remains the only curative therapy for MPNs but is associated with substantial morbidity and mortality.”
Recent data have shown that glutaminolysis plays a chief role in cancer cell metabolism. In this 2-step reaction process, GLS acts as a catalyst, helping to turn glutamine into glutamate. Subsequently, glutamate fuels energy production in the tricarboxylic acid cycle. “As many cancers have proven to be dependent on this pathway, targeting GLS has become an attractive therapeutic avenue,” the researchers wrote.
In this analysis, Dr. Ciboddo and colleagues assessed mRNA levels of GLS in peripheral blood mononuclear cells from 30 patients with MPN and 5 healthy donors. They tested GLS by stably overexpressing either JAK2-, CALR-, or MPL-mutated proteins. CALR overexpression was treated with the JAK inhibitor ruxolitinib. Subsequently, the sensitivity of MPN cells to GLS inhibition was assessed with a GLS inhibitor, CB-839, which is currently in advanced-phase clinical trials for other cancers, including myelodysplastic syndrome.
According to the findings, GLS mRNA expression increased in all patients with MPNs regardless of the driver mutation. The researchers observed that GLS expression in JAK2-V617F patients was higher in those patients with myelofibrosis than in those with essential thrombocythemia. Moreover, GLS protein expression and activity were increased in TF-1 cells expressing JAK2, MPL, and CALR mutations. “We also found that GLS mRNA and protein expression was up-regulated in a JAK/STAT-dependent manner,” the researchers wrote. “Interestingly, despite increased expression of GLS across all MPN driver mutations, only JAK2-V617F cells demonstrated significant sensitivity to GLS inhibition with CB-839 in vitro and with preliminary data in vivo. We found that combination treatment with [the] JAK inhibitor ruxolitinib further inhibited cell viability.” They concluded that “treatment with CB-839 may thus represent a novel therapeutic avenue for JAK2-V617F [positive] MPNs.”
Source: Ciboddo M, Yan G, Coen C, et al. GLS in Philadelphia-negative and JAK2 V617F-driven myeloproliferative neoplasms (MPNs). Abstract #e15092. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.