Resistance to combined phosphoinositide 3-kinase and mammalian target of rapamycin inhibition. Resistance to combined phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibition occurs in a two-wave mechanism. Initially, blockade of PI3K and mTOR lead to diversion of mitogenic serine/threonine phosphorylation via Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (Stat5). Stat5 activation then induces transcriptional changes with activation of the IL-8 signaling axis. In this process, tumor cells secrete IL-8 that then stimulates tumor cells via the G-protein coupled receptor CXCR1. PI3K and mTOR inhibition thus diverts mitogenic signaling to a new feed-forward loop that sustains tumor cell growth via IL-8 signaling. IGF-1, insulin-like growth factor-1; PKB, protein kinase B; TSC, tuberous sclerosis protein.