mTOR inhibitor

**Mechanism** - mTOR (mechanistic/mammalian target of rapamycin) is a serine/threonine kinase downstream of PI3K/AKT. It exists as mTORC1 (rapamycin-sensitive; regulates protein synthesis, cell growth, and proliferation) and mTORC2 (largely rapamycin-insensitive acutely; activates AKT). - Sirolimus (rapamycin) and its analogs (everolimus, temsirolimus) bind the intracellular protein FKBP-12. The drug–FKBP-12 complex inhibits mTORC1. - In T cells, this blocks the response to IL-2 (signal 3) and arrests the cell cycle at G1→S. Calcineurin inhibitors (cyclosporine, tacrolimus) instead block IL-2 transcription by inhibiting calcineurin/NFAT. - Tacrolimus and sirolimus both bind FKBP-12, but the complexes have different targets: tacrolimus–FKBP12 inhibits calcineurin, and sirolimus–FKBP12 inhibits mTOR.

**Agents and uses** - Sirolimus: prophylaxis of organ rejection (especially renal transplant), a calcineurin-inhibitor-sparing regimen; also lymphangioleiomyomatosis (LAM); coating on drug-eluting coronary stents to prevent restenosis (inhibits smooth muscle proliferation). - Everolimus: transplant (kidney, liver) with reduced-dose CNI; advanced renal cell carcinoma; HR+/HER2– breast cancer (with exemestane); pancreatic neuroendocrine tumors; tuberous sclerosis complex (TSC) manifestations (subependymal giant cell astrocytoma, renal angiomyolipoma, refractory seizures). - Temsirolimus: IV; advanced renal cell carcinoma. - TSC1/TSC2 (hamartin/tuberin) normally inhibit mTOR, so loss-of-function mutations cause constitutive mTOR activation. This is the rationale for treating TSC with mTOR inhibitors. PTEN loss (e.g., Cowden syndrome) also upregulates PI3K/AKT/mTOR.

**Adverse effects (high-yield)** - Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia). - Myelosuppression: thrombocytopenia, leukopenia, anemia. - Impaired wound healing and lymphocele; dehiscence is a concern in the early post-transplant period. - Stomatitis and mouth ulcers. - Noninfectious interstitial pneumonitis. - Hyperglycemia/new-onset diabetes. - Increased infection risk and malignancy (immunosuppression), though a lower malignancy risk than with CNIs. - Proteinuria. Sirolimus is NOT significantly nephrotoxic by itself, but it can potentiate CNI nephrotoxicity. - Mnemonic: "Sirolimus: Sir Lymph-a-lot, Slow healing, Stomatitis, and Sky-high lipids."

**Drug interactions and pharmacology** - Metabolized by CYP3A4 and a P-gp substrate. CYP3A4 inhibitors (azoles, macrolides, diltiazem, grapefruit juice) raise levels. Inducers (rifampin, phenytoin, carbamazepine) lower levels. - Oral with a long half-life; levels are monitored by therapeutic drug monitoring. - Avoid live vaccines.

**Comparison with CNIs (frequently tested)** - Cyclosporine/tacrolimus: nephrotoxicity, neurotoxicity (tremor), hypertension, hyperkalemia, and diabetes (especially tacrolimus). Cyclosporine also causes gingival hyperplasia and hirsutism. - Sirolimus: "kidney-sparing" but causes hyperlipidemia, cytopenias, and poor wound healing.

**Clinical pearls** - Think mTOR inhibitor when a question describes a transplant patient with new hyperlipidemia, cytopenias, and mouth ulcers or pneumonitis. Also think of it for a TSC patient with SEGA or angiomyolipoma, and for a patient with renal cell carcinoma.