title: JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer.
abstract: Hyperactive PI3K/mTOR signaling is prevalent in human malignancies and its inhibition has potent antitumor consequences. Unfortunately, single-agent targeted cancer therapy is usually short-lived. We have discovered a JAK2/STAT5-evoked positive feedback loop that dampens the efficacy of PI3K/mTOR inhibition. Mechanistically, PI3K/mTOR inhibition increased IRS1-dependent activation of JAK2/STAT5 and secretion of IL-8 in several cell lines and primary breast tumors. Genetic or pharmacological inhibition of JAK2 abrogated this feedback loop and combined PI3K/mTOR and JAK2 inhibition synergistically reduced cancer cell number and tumor growth, decreased tumor seeding and metastasis, and also increased overall survival of the animals. Our results provide a rationale for combined targeting of the PI3K/mTOR and JAK2/STAT5 pathways in triple-negative breast cancer, a particularly aggressive and currently incurable disease.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, CH-4058, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Britschgi
authors.forename: Rita
authors.initials: R
authors.lastname: Andraos
authors.forename: Heike
authors.initials: H
authors.lastname: Brinkhaus
authors.forename: Ina
authors.initials: I
authors.lastname: Klebba
authors.forename: Vincent
authors.initials: V
authors.lastname: Romanet
authors.forename: Urs
authors.initials: U
authors.lastname: Müller
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bentires-Alj
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; D016209:Interleukin-8; D053614:Janus Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D023062:Receptors, Interleukin-8A; D050799:STAT5 Transcription Factor; D058570:TOR Serine-Threonine Kinases