JAK2-STAT5 signaling: A novel mechanism of resistance to targeted PI3K/mTOR inhibition

Abstract

A recent article published by Britschgi et al. in Cancer Cell, "JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer," describes a positive feedback loop of JAK2/STAT5 activation that drives resistance to PI3K/mTOR inhibition in breast cancer. The authors found that genetic or pharmacological inhibition of JAK2 circumvents resistance to PI3K/mTOR inhibition and go on to show the efficacy of combined PI3K/mTOR and JAK2 inhibition on reducing cancer cell number, tumor growth, and metastasis as well as increasing in vivo survival. These results provide strong support for combination therapy with JAK2/STAT5 and PI3K/mTOR inhibitors in breast cancer. Here we discuss how the article by Britschgi et al. proposes a novel mechanism to explain how breast cancer cells overcome inhibition of a key signaling pathway driving cell proliferation. We also discuss the interplay between activation of the transcription factors STAT5 and STAT3 in breast cancer.

Keywords: breast cancer; kinases; signal transduction; targeted therapy; transcription factors.

Figure 1. A bimodal JAK2/STAT5 resistance mechanism to PI3K/mTOR inhibition. PI3K/mTOR inhibition leads to (1) accumulation of insulin receptor (IR), insulin-like growth factor 1 receptor (IGF-1R), and insulin receptor substrate 1 (IRS1), which catalyzes JAK2/STAT5 phosphorylation and restoration of Akt phosphorylation and (2) STAT5 transcriptional upregulation of IL-8, which further activates JAK2/STAT5 via a positive feedback loop.