Abstract LB-36: JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: A rationale for co-targeting these pathways in metastatic breast cancer.

Abstract

Abstract Hyperactive PI3K/mTOR signaling is prevalent in the majority of human malignancies (1) and its inhibition exhibits potent antitumor activity in a wide spectrum of solid cancers. Unfortunately, single-agent targeted cancer therapy is usually short-lived and thwarted by different resistance mechanisms (2). Here, we report the discovery of a JAK2/STAT5-evoked positive feedback loop that causes adaptive resistance to dual 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 triple-negative breast tumors. Genetic or pharmacological inhibition of JAK2 abrogated this vicious feedback loop. Combined PI3K/mTOR and JAK2 inhibition synergistically reduced cancer cell viability in vitro as well as tumor growth in vivo, and decreased tumor seeding and metastasis due to its impact on the IL-8 receptor CXCR1+ tumor-initiating subpopulation of cells. We further found that combined PI3K/mTOR and JAK2 inhibition increased event-free as a well as overall survival of tumor bearing animals. This study reveals a new link between growth factor signaling, JAK/STAT activation, cytokine secretion and metastasis. 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. Citation Format: Adrian Britschgi, Rita Andraos, Heike Brinkhaus, Inna Klebba, Masato Murakami, Vincent Romanet, Urs Müller, Thomas Radimerski, Mohamed Bentires-Alj. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: A rationale for co-targeting these pathways in metastatic breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-36. doi:10.1158/1538-7445.AM2013-LB-36