Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance

Abstract

Gliomas represent the most common primary brain tumor and among the most aggressive of cancers. Patients with glioma typically relapse within a year of initial diagnosis. Recurrent glioma is associated with acquired therapeutic resistance. Although neurosurgical resection, radiation and chemotherapy provide clear benefit, survival remains disappointing. It is, therefore, critical that we identify effective medical therapies and appropriate tumor biomarkers in patients at initial presentation, to promote durable responses in glioma. Pathways linking receptor tyrosine kinases, PI3 kinase, Akt, and mTOR feature prominently in this disease and represent therapeutic targets. Small molecules that inhibit one or more of these kinases are now being introduced into the clinic and may have some activity. Disappointingly, however, preclinical studies demonstrate these agents to be primarily cytostatic rather than cytotoxic to glioma cells. Here, we detail activation of the EGFR-PI3K-Akt-mTOR signaling network in glioma, review class I PI3K inhibitors, discuss roles for Akt, PKC and mTOR, and the importance of biomarkers. We further delineate attempts to target both single and multiple components within the EGFR-PI3K-Akt-mTOR axes. Lastly, we discuss the need to combine targeted therapies with cytotoxic chemotherapy, radiation and with inhibitors of survival signaling to improve outcomes in glioma.

Fig. 1

PI3 kinase signaling pathway in glioma. Class I PI3 kinases are activated by upstream signals from receptor tyrosine kinases (RTKs) including EGFR and other RTKs. PI3 kinase catalyzes production of the second messenger PIP₃, which actives both Akt and PKC. Akt and PKC phosphorylate multiple downstream substrates. We found Akt was dispensable for mitogenic signaling between EGFR and mTOR in glioma cells, whereas PKC was critical (33). PIP₃ is negatively regulated by the tumor suppressor PTEN, a phosphatase driving dephosphorylation of PIP₃

Fig. 2

Sites of action for inhibitors and shRNAs in the EGFR-PI3K-Akt-mTOR pathway. Agents that inhibit the EGFR-PI3K-Akt-mTOR pathway at multiple sites may contribute to anticancer effects in malignant glioma. Agents that inhibit only one target within the EGFR-PI3K-Akt-mTOR axis generally show only modest efficacy and fail to induce appreciable apoptosis. This disappointing efficacy stems in-part from multiple nodes of activation in the EGFR-PI3K-Akt-mTOR axis. For example, loss of PTEN activates PI3K signaling. A feedback loop between S6K and IRS-1 also lead to PI3K activation. Inhibition of the PI3K-Akt-mTOR pathway may also induce autophagy, enabling cancer cells to survive some small molecule inhibitors of this pathway