Mechanism of Action Magnifier – 2016 Desk Reference
Ruxolitinib: a Kinase Inhibitor That Inhibits Overactive JAK Pathway Signaling
Overactive JAK pathway signaling is a key mechanism of disease in the myeloproliferative neoplasms (MPNs) polycythemia vera and myelofibrosis.1,2
Signaling of the JAK pathway plays a key role in normal cell functioning.3-6 Well-regulated JAK signaling is essential for cell production, cell proliferation, and immune function. Intracellular regulators, such as suppressor of cytokine signaling (SOCS), help regulate JAK signaling.3,4
Cytokines bind to receptors and activate JAKs. JAKs activate signal transducers and activators of transcription (STATs), which dimerize and enter the nucleus. Inside the nucleus, the STATs bind to DNA, stimulating the expression of genes related to cell survival, differentiation, and proliferation.4,7-9
The complex JAK pathway may become overactivated by many mechanisms.3,10-17 Somatic mutations primarily involve JAK2, CALR, or MPL.3,10-17 Approximately 90% of patients with myelofibrosis carry one of these mutations.18 Approximately 95% of patients with polycythemia vera have the JAK2 V617F mutation.1 Other mechanisms may include increased JAK1 signaling, an excess of cytokines activating the receptors, or impaired intracellular regulators such as SOCS.3,10-17
Ruxolitinib, a kinase inhibitor, inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2), which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function.19
In a mouse model of JAK2 V617Fâ€“positive MPN, oral administration of ruxolitinib19:
- Prevented splenomegaly
- Decreased circulating inflammatory cytokines (eg, tumor necrosis factor alpha and interleukin-6)
- Preferentially decreased JAK2 V617F mutant cells in the spleen.
Ruxolitinib is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.
Ruxolitinib is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.
- Rampal R, Al-Shahrour F, Abdel-Wahab O, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood. 2014;123:e123-e133.
- Keohane C, Radia DH, Harrison CN. Treatment and management of myelofibrosis in the era of JAK inhibitors. Biologics. 2013;7:189-198.
- Fourouclas N, Li J, Gilby DC, et al. Methylation of the suppressor of cytokine signaling 3 gene (SOCS3) in myeloproliferative disorders. Haematologica. 2008;93:1635-1644.
- Furqan M, Mukhi N, Lee B, et al. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res. 2013;1:5.
- Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol. 2008;19:385-393.
- Delhommeau F, Jeziorowska D, Marzac C, et al. Molecular aspects of myeloproliferative neoplasms. Int J Hematol. 2010;91:165-173.
- Kisseleva T, Bhattacharya S, Braunstein J, et al. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002;285:1-24.
- Pellegrini S, Dusanter-Fourt I. The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J Biochem. 1997;248:615-633.
- QuintÃ¡s-Cardama A, Kantarjian H, Cortes J, et al. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10:127-140.
- Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790.
- ChalignÃ© R, Tonetti C, Besancenot R, et al. New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition. Leukemia. 2008;22:1557-1566.
- Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459-468.
- Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:e270.
- Kralovics R. Genetic complexity of myeloproliferative neoplasms. Leukemia. 2008;22:1841-1848.
- QuintÃ¡s-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115:3109-3117.
- Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27:1874-1881.
- Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program. 2009:636-642.
- Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89:915-925.
- Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2014.
Nivolumab plus Trastuzumab with S-1/Capecitabine plus Oxaliplatin for HER2-Positive Advanced Gastric Cancer: The Ni-HIGH Study
Results of the Ni-HIGH study showed that the combination of nivolumab plus trastuzumab and either S-1 or capecitabine plus oxaliplatin was tolerable and showed promising antitumor activity in chemotherapy-naÃ¯ve patients with HER2-positive advanced gastric cancer.
Less Is More: 6 Months of Trastuzumab Treatment Equivalent to 12 Months in HER2-Positive Breast Cancer
Analysis of the phase 3 randomized clinical trial PERSEPHONE showed that 6 months of treatment with trastuzumab was noninferior to 12 months in terms of disease-free survival, whereas a shorter course of trastuzumab was associated with a 50% reduction in cardiotoxicity.