Molecular Pathways: JAK/STAT Pathway: Mutations, Inhibitors, and Resistance

• Published in: Clinical cancer research Vol. 19; no. 8; pp. 1933 - 1940
• Main Authors: Quintás-Cardama, Alfonso, Verstovsek, Srdan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.04.2013
• Subjects: Antineoplastic agents; Biological and medical sciences; Chemotherapy; Drug Resistance, Neoplasm - genetics; Humans; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Medical sciences; Models, Biological; Mutation; Myeloproliferative Disorders - drug therapy; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - metabolism; Pharmacology. Drug treatments; Pyrazoles - therapeutic use; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - physiology; STAT5 Transcription Factor - metabolism; Antineoplastic agent; Human; Jak protein tyrosine kinase; Treatment resistance; Myelofibrosis; Tyrosine kinase inhibitor; Hemopathy; Review; Myeloproliferative syndrome; Signal transduction; Ruxolitinib; Clinical trial; Genetics; Transduction factor STAT; Mutation; Janus kinase inhibitor
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-0284

Aberrant activation of the JAK/STAT pathway has been reported in a variety of disease states, including inflammatory conditions, hematologic malignancies, and solid tumors. For instance, a large proportion of patients with myeloproliferative neoplasms (MPN) carry the acquired gain-of-function JAK2 V617F somatic mutation. This knowledge has dramatically improved our understanding of the pathogenesis of MPNs and has facilitated the development of therapeutics capable of suppressing the constitutive activation of the JAK/STAT pathway, now recognized as a common underlying biologic abnormality in MPNs. Ruxolitinib is an oral JAK1 and JAK2 inhibitor that has recently been approved for the treatment of myelofibrosis and has been tested against other hematologic malignancies. A series of agents with different specificities against different members of the JAK family of proteins is currently undergoing evaluation in clinical trials for patients with MPNs, lymphoma, and solid tumors such as breast or pancreatic cancer. Despite the significant clinical activity exhibited by these agents in myelofibrosis, some patients fail to respond or progress during JAK kinase inhibitor therapy. Recent reports have shed light into the mechanisms of resistance to JAK inhibitor therapy. Several approaches hold promise to overcome such resistance. Clin Cancer Res; 19(8); 1933–40. ©2013 AACR.