Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NF?B pathway inhibition

Targeted inhibitors of JAK2 (e.g. ruxolitinib) often provide symptomatic relief for myeloproliferative neoplasm (MPN) patients, but the malignant clone persists and remains susceptible to disease transformation. These observations suggest that targeting alternative dysregulated signaling pathways may provide therapeutic benefit. Previous studies identified NF?B pathway hyperactivation in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) that was insensitive to JAK2 inhibition. Here, we provide evidence that NF?B pathway inhibition via pevonedistat targets malignant cells in MPN patient samples as well as in syngeneic MPN and patient-derived xenograft mouse models that is non-redundant with ruxolitinib. Colony forming assays revealed preferential inhibition of MF colony growth compared to normal colony formation. In mass cytometry studies, pevonedistat blunted canonical TNF? responses in MF and sAML patient CD34+ cells. Pevonedistat also inhibited hyperproduction of inflammatory cytokines more effectively than ruxolitinib. Upon pevonedistat treatment alone or in combination with ruxolitinib, MPN mouse models exhibited reduced disease burden and improved survival. These studies demonstrating efficacy of pevonedistat in MPN cells in vitro as well as in vivo provide a rationale for therapeutic inhibition of NF?B signaling for MF treatment. Based on these findings, a Phase I clinical trial combining pevonedistat with ruxolitinib has been initiated. Overall design: mRNA profiling of HEL cells treated with ruxolitinib, pevonedistat, or combination.