Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors

Abstract

BackgroundActivating mutations in JAK1 and JAK2 have been described in patients with various hematologicmalignancies including acute lymphoblastic leukemia and myeloproliferative neoplasms,leading to clinical trials with JAK inhibitors. While there has been a tremendous effort towardsthe development of specific JAK inhibitors, mutations conferring resistance to such drugs havenot yet been observed.Design and MethodsTaking advantage of a model of spontaneous cellular transformation, we sequenced JAK1 inselected tumorigenic BaF3 clones and identified 25 de novo JAK1 activating mutations, including5 mutations already described in human leukemias. We further used this library of JAK1 mutation-positive cell lines to assess their sensitivity to ATP-competitive inhibitors.ResultsWhile most JAK1 mutants were sensitive to ATP-competitive JAK inhibitors, mutations targetingPhe958 and Pro960 in the hinge region of the kinase domain rendered JAK1 constitutivelyactive but also resistant to all tested JAK inhibitors. Furthermore, mutation of the homologousTyr931 in JAK2 wild-type or JAK2 V617F mutant found in patients with myeloproliferativeneoplasms also conferred resistance to JAK inhibitors, such as INCB018424, which is currentlyin clinical use.ConclusionsOur data indicate that some activating mutations not only promote autonomous cell proliferationbut also confer resistance to ATP-competitive inhibitors. In vivo, such a mutation canpotentially occur as primary JAK-activating mutations but also as secondary mutations combiningoncogenicity with drug resistance. ©2011 Ferrata Storti Foundation.