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-
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.
Source: JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer. Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, Müller U, Murakami M, Radimerski T, Bentires-Alj M (firstname.lastname@example.org). Cancer Cell. 2012 Dec 11;22(6):796-811.
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