Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms

by Selleckchem | Jul 15 2023

Small molecule inhibitors targeting JAK2 provide symptomatic benefits for myeloproliferative neoplasm (MPN) patients and are among first-line therapeutic agents. However, despite all having potent capacity to suppress JAK-STAT signaling, they demonstrate distinct clinical profiles suggesting contributory effects in targeting other ancillary pathways. Here, we performed comprehensive profiling on four JAK2 inhibitors either FDA-approved (ruxolitinib, fedratinib, and pacritinib) or undergoing phase 3 studies (momelotinib) to better outline mechanistic and therapeutic efficacy. Across JAK2-mutant in vitro models, all four inhibitors demonstrated similar anti-proliferative phenotypes, whereas pacritinib yielded greatest potency on suppressing colony formation in primary samples, while momelotinib exhibited unique erythroid colony formation sparing. All inhibitors reduced leukemic engraftment, disease burden, and extended survival across patient-derived xenograft (PDX) models, with strongest effects elicited by pacritinib. Through RNA-sequencing and gene set enrichment analyses, differential suppressive degrees of JAK-STAT and inflammatory response signatures were revealed, which we validated with signaling and cytokine suspension mass cytometry across primary samples. Lastly, we assessed the capacity of JAK2 inhibitors to modulate iron regulation, uncovering potent suppression of hepcidin and SMAD signaling by pacritinib. These comparative findings provide insight into the differential and beneficial effects of ancillary targeting beyond JAK2 and may help guide the use of specific inhibitors in personalized therapy.

Comments:

The study you mentioned aimed to provide a comprehensive profiling of four small molecule inhibitors targeting JAK2 in order to understand their mechanistic and therapeutic efficacy in myeloproliferative neoplasm (MPN) patients. The four inhibitors investigated were ruxolitinib, fedratinib, pacritinib (all FDA-approved), and momelotinib (undergoing phase 3 studies).

The results of the study showed that all four JAK2 inhibitors demonstrated similar anti-proliferative effects in JAK2-mutant in vitro models. However, pacritinib exhibited the greatest potency in suppressing colony formation in primary samples, while momelotinib showed a unique ability to spare erythroid colony formation.

In patient-derived xenograft (PDX) models, all four inhibitors reduced leukemic engraftment, disease burden, and extended survival. Pacritinib had the strongest effects among the inhibitors studied.

By performing RNA-sequencing and gene set enrichment analyses, the researchers identified differential suppressive effects on JAK-STAT and inflammatory response signatures among the inhibitors. These findings were further validated using signaling and cytokine suspension mass cytometry in primary samples.

Additionally, the study investigated the capacity of JAK2 inhibitors to modulate iron regulation. Pacritinib was found to strongly suppress hepcidin and SMAD signaling, which are involved in iron regulation.

Overall, the comparative findings of this study provide insights into the distinct clinical profiles and beneficial effects of the JAK2 inhibitors beyond JAK2 itself. The results suggest that these inhibitors may target ancillary pathways and have differential effects on various cellular processes. These findings can potentially guide the personalized use of specific JAK2 inhibitors in MPN therapy.