JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer

Menée sur des lignées cellulaires et des modèles murins de cancer du sein triplement négatif, cette étude suggère que l'inhibition de la signalisation JAK2/STAT5 permet de surmonter l'apparition d'une résistance à un inhibiteur de la signalisation PI3K/mTOR

Résumé en anglais

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.

º PI3K/mTOR inhibition induces biphasic activation of JAK2/STAT5
º JAK2/STAT5/IL8 evokes a multimodal mechanism of resistance to PI3K/mTOR inhibition
º Cotargeting PI3K/mTOR and JAK2 triggers cell death and reduces tumor growth
º Coinhibition of PI3K/mTOR and JAK2 decreases metastasis and increases survival