Targeting PI3K, HER2 and the IL-8/JAK2 axis in metastatic breast cancer: Which combination makes the whole greater than the sum of its parts?

The widespread hyperactivation of the PI3K/mTOR pathway in human cancer has made it a prime target for the treatment of this disease. However, a variety of resistance mechanisms involving (re)activation of the targeted pathway or of parallel survival signaling cascades have limited the clinical success of inhibitors targeting PI3K and/or mTOR. Recent studies delineated new crosstalks between PI3K, HER2, JAK2 and IL-8 signaling, which can explain the limited efficacy of PI3K blockade when inhibitors of this pathway are used as single agents. In this review, we summarize molecular mechanisms of resistance to inhibitors of the PI3K/mTOR pathway, provide an outline of new connections between crucial oncogenic signaling pathways, and discuss the potential of new combination therapy approaches to overcome resistance.