Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms.

Autor: Kong T; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Yu L; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Laranjeira ABA; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Fisher DAC; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., He F; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Cox MJ; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Oh ST; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.; Immunomonitoring Laboratory, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Jazyk: angličtina
Zdroj: American journal of hematology [Am J Hematol] 2023 Jul; Vol. 98 (7), pp. 1029-1042. Date of Electronic Publication: 2023 May 19.
DOI: 10.1002/ajh.26935
Abstrakt: 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.
(© 2023 Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz: