Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations

Abstract

The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection.

Figure 1. Pharmacological inhibition of the PI3K/Akt/mTOR pathway

Receptor tyrosine kinases (RTK) such as IGF-IR and EGFR, integrins, and G-protein coupled receptors (GPCR) can all stimulate PI3K. PI3K phosphorylates PI(4)P and PI(4,5)P2 at the 3′-position to generate PI(3,4)P2 and PI(3,4,5)P3, respectively. PTEN opposes the function of PI3K by removing 3′-phosphate groups. LY294002 is a reversible small molecule inhibitor of PI3K, while wortmannin and its analogue, PX-866, are irreversible inhibitors. Generation of 3′-phosphoinositides activates both Akt and PDK-1, which phosphorylates Akt at T308. Akt propagates its signal to affect transcription, apoptosis, and cell cycle progression. Perifosine and phosphatidylinositol ether lipid analogues (PIAs) are lipid-based Akt inhibitors that interact with the PH domain of Akt and prevent its translocation to the membrane, while API-2, also known as triciribine, is a small molecule that inhibits the kinase activity of Akt. Akt can activate mTOR directly by phosphorylation at S2448 or indirectly, by phosphorylation and inactivation of TSC2. When TSC2 is inactivated, the GTPase Rheb is maintained in its GTP-bound state, allowing for increased activation of mTOR. mTOR (TORC1) activates S6 kinase 1, which activates ribosomal protein S6 and leads to increased protein translation. TORC1 also phosphorylates 4EBP-1, causing it to dissociate from eIF4E, and freeing eIF4E to participate in formation of the translation initiation complex. Inhibitors of mTOR include rapamycin and its analogues, RAD-001 and CCI-779, all of which bind to the FK506-binding protein, FKBP-12, which then binds and inhibits mTOR.

Figure 2. Combinatorial approaches with inhibitors of the PI3K/Akt/mTOR pathway

Several approaches can be employed when combining pathway inhibitors with other targeted therapies. Inhibition of proximal pathway components, such as receptor tyrosine kinases (RTKs) and oncogenes, combined with distal inhibition of Akt or mTOR may be an effective approach to circumvent feedback activation that could occur with distal inhibition alone (left panel). Alternatively, dual inhibition of parallel signaling pathways prevents compensatory activation of redundant pro-survival pathways (middle panel). Finally, pathway inhibition can be combined with several other types of targeted therapies, including inhibition of histone deacetylase complexes (HDAC), the proteasome and cyclooxygenase-2 (COX-2) (right panel).