Targeting the PI3K-AKT-mTOR signaling network in cancer

Abstract

The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumor types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.

Figure 1. Schematic diagram of signaling through the phosphoinositide 3-kinase-AKT (PI3K-AKT) pathway with current and future treatment strategies.

PI3K signaling impacts on cell growth, survival, differentiation, and proliferation. The pointed arrows represent activation of substrates, while blunt arrows represent inhibition. Activation of membrane kinases, such as insulin-like growth factor-1 (IGF1), by external growth factors can initiate activation of intracellular signaling pathways. AKT is phosphorylated downstream of PI3K with various effects, including the activation of mammalian target of rapamycin (mTOR). mTOR phosphorylates p70S6 and 4E-binding protein 1 (4EBP-1), which then leads to an increased translation of mRNA that encodes several cell cycle regulators. These effects are controlled by the tuberous sclerosis 1 (TSC1)-TSC2 complex. The Ras-Raf-MEK-MAPK pathway has its own distinct downstream effects, but also converges with the PI3K-AKT pathway. Future combination regimens involving targeted agents against this signaling network include the concomitant or sequential blockade of these pathways. PTEN, phosphatase and tensin homolog; HIF-1α, hypoxia-inducible factor-1α; MAPK, mitogen-activated protein kinase.