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Published on: January 9, 2019
PI3K signaling in glioma--animal models and therapeutic challenges
Christine K Cheng1, Qi-Wen Fan, William A Weiss
1Department of Neurology, University of California, San Francisco, CA 94143, USA. ccheng@ucsf.edu
Abstract:
The PI3 kinase (PI3K) family plays a complex role in cell biology and metabolism. Signaling through the PI3Ks is frequently activated in many human cancers, including glioblastoma, because of gain-of-function mutations in PIK3CA or loss of PTEN. Experiments involving genetic mouse models and small molecule inhibitors have helped to elucidate the roles of the regulatory and catalytic subunits of PI3K in metabolism and cancer. Downstream of PI3K is Akt, a critical effector of growth, proliferation and survival. The suggested dependence of glioblastoma tumors on PI3K signaling implies that PI3K inhibitors should lead to effective killing of these cancer cells, but that has been shown not to be the case. The engagement of other survival pathways in response to PI3K inhibition prompts the need to develop combination therapies that promote cytotoxicity in cancer cells.
Insights
Phosphoinositide 3-kinase (PI3K) signaling is crucial in glioblastoma, but PI3K inhibitors alone are ineffective. Combination therapies are needed to overcome resistance and enhance cancer cell killing.
Area of Science:
- Oncology
- Molecular Biology
- Cell Metabolism
Background:
- The phosphoinositide 3-kinase (PI3K) pathway is integral to cell biology and metabolism.
- Aberrant PI3K signaling, driven by PIK3CA mutations or PTEN loss, is common in human cancers like glioblastoma.
- PI3K signaling regulates critical cellular processes including growth, proliferation, and survival via downstream effectors like Akt.
Purpose of the Study:
- To investigate the role of PI3K signaling in glioblastoma metabolism and cancer.
- To understand the limitations of PI3K inhibitors as monotherapy in glioblastoma treatment.
- To explore the rationale for developing combination therapies targeting PI3K-driven cancers.
Main Methods:
- Utilized genetic mouse models to study PI3K subunit functions.
- Employed small molecule inhibitors to probe PI3K pathway activity.
- Analyzed downstream signaling effectors such as Akt.
Main Results:
- PI3K pathway activation is a key feature of glioblastoma.
- Direct inhibition of PI3K shows limited efficacy in eliminating glioblastoma cells.
- PI3K inhibition triggers compensatory survival pathways, contributing to therapeutic resistance.
Conclusions:
- Glioblastoma exhibits a strong dependence on PI3K signaling.
- Targeting PI3K alone is insufficient for effective glioblastoma treatment.
- Combination strategies are essential to overcome PI3K pathway-mediated resistance and induce cancer cell death.
