What it is
- mTOR is a serine/threonine kinase that sits at the center of the PI3K/AKT/mTOR pathway, a key signaling cascade in cell growth, proliferation, survival, and angiogenesis.
- It acts as a nutrient/energy/redox sensor and regulates protein translation and metabolism.
Complexes
mTOR exists in two distinct complexes:
- mTORC1 – regulates cell growth, metabolism, angiogenesis.
- Sensitive to rapamycin and its analogs (temsirolimus, everolimus).
- mTORC2 – regulates cytoskeleton, AKT activation.
- Less sensitive to rapamycin.
Role in Cancer
- PI3K/AKT/mTOR pathway is hyperactivated in many cancers due to mutations in:
- PIK3CA (PI3K)
- PTEN loss
- AKT overactivation
- Overactive mTOR → increased protein synthesis, angiogenesis, tumor progression, and resistance to apoptosis.
Targeted Inhibition
- mTOR inhibitors (rapalogs): Everolimus, Temsirolimus, Sirolimus (mainly transplant).
- Mechanism: Bind FKBP12 → inhibit mTORC1 → ↓ protein synthesis and cell growth.
- Clinical uses: RCC, HR+/HER2– breast cancer, pancreatic NETs, SEGA, tuberous sclerosis.
Key Toxicities (Class)
- Mucositis/stomatitis (very common).
- Metabolic issues: hyperglycemia, hyperlipidemia, hypertriglyceridemia.
- Myelosuppression (esp. anemia, thrombocytopenia).
- Non-infectious pneumonitis (unique toxicity).
- Infections due to immunosuppression.
- Delayed wound healing.
Pharmacist Clinical Pearl
- Everolimus (oral) = more common in solid tumors.
- Temsirolimus (IV) = mainly RCC, needs diphenhydramine premedication.
- Always monitor glucose, lipids, CBC, and counsel on stomatitis management.