G3BP Proteins Could Improve the Efficacy of MTOR Inhibiting Drugs

According to a new study published in Cell, G3BP proteins inhibit the metabolic driver MTOR— a signaling protein that plays a central role in tumor diseases and developmental disorders of the brain. The study was led by researchers from the University of Innsbruck. 

"Because MTOR is such a central switch for metabolism, errors in its activation lead to serious diseases. These include cancers associated with excessive metabolic activity, cell growth and proliferation. Dysregulated MTOR also causes malformations of the nervous system, disturbing stimulus processing and eliciting behavioral disorders and epilepsy," explains Kathrin Thedieck, lead researcher. 

The teams aimed to investigate how the tuberous sclerosis complex (TSC) binds to lysosomes, in order to regulate its activity. They discovered that the G3BP (Ras GTPase-activating protein-binding protein) proteins localize to lysosomes, together with the TSC complex. There, the G3BP proteins form an anchor that ensures that the TSC complex can bind to the lysosomes. This anchor function plays a crucial role in breast cancer. If the amount of G3BP decreases, not only MTOR activity but also cell motility is increased in cancer cell cultures. MTOR inhibitors suppress this hypermotility. In breast cancer patients, low G3BP correlates with a worse prognosis. "G3BP proteins could therefore be valuable markers to personalize therapies and improve the efficacy of drugs that inhibit MTOR," says Christiane Opitz.

G3BP proteins also inhibit MTOR in the brain. In zebrafish, the scientists observed disturbances in brain development when G3BP was missing. Loss of G3BP also resulted in neuronal hyperactivity and ensuing behavioral abnormalities reminiscent of epilepsy in humans. Compounds that target MTOR suppress neuronal hyperactivity.  "We therefore anticipate that patients with neurological disorders and G3BP malfunction could benefit from MTOR inhibitors and we look forward to further exploring this together with our scientific network," says Thedieck.