mTOR inhibitors

**Mechanism:** mTOR (mechanistic target of rapamycin) is a serine/threonine kinase in the PI3K/AKT pathway. It regulates cell growth, protein synthesis, angiogenesis, and proliferation. Two complexes exist: mTORC1 (rapamycin-sensitive; regulates protein synthesis via S6K and 4E-BP1) 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 receptor signaling, so cells arrest in G1 and fail to proliferate. Compare tacrolimus: it also binds FKBP-12 but the complex inhibits calcineurin, which blocks IL-2 transcription (via NFAT). Cyclosporine binds cyclophilin and also inhibits calcineurin.

**Agents and uses:** - Sirolimus (rapamycin): prophylaxis of kidney transplant rejection. It is often used as a calcineurin-inhibitor-sparing agent because it is not nephrotoxic. It is also used in drug-eluting coronary stents to prevent restenosis (inhibits smooth muscle proliferation), and in lymphangioleiomyomatosis (LAM). - Everolimus: transplant rejection prophylaxis (kidney, liver, heart). In oncology it is used for advanced renal cell carcinoma, HR+/HER2− breast cancer (with exemestane), pancreatic neuroendocrine tumors, and tuberous sclerosis complex (TSC) lesions such as subependymal giant cell astrocytoma (SEGA), renal angiomyolipoma, and seizures. - Temsirolimus: IV, advanced renal cell carcinoma.

**Clinical associations:** TSC (TSC1/hamartin and TSC2/tuberin loss-of-function) causes constitutive mTOR activation, so mTOR inhibitors are used for TSC tumors. PTEN loss (as in Cowden syndrome) and PI3K/AKT activation also upregulate mTOR. VHL loss in clear cell RCC raises HIF and VEGF, and mTOR inhibition lowers HIF translation.

**Adverse effects (high-yield):** - Hyperlipidemia (hypertriglyceridemia and hypercholesterolemia) and hyperglycemia/new-onset diabetes - Myelosuppression: thrombocytopenia, leukopenia, anemia - Impaired wound healing and dehiscence, lymphocele (wound complications; delay start after transplant) - Stomatitis/mucositis (mouth ulcers) - Noninfectious interstitial pneumonitis - Proteinuria - Increased risk of infection and malignancy (as with other immunosuppressants) - Notable for NOT causing significant nephrotoxicity as a monotherapy. However, combined with a calcineurin inhibitor, they can potentiate CNI nephrotoxicity. - Hepatic artery thrombosis in liver transplant (boxed warning when started early)

**Pharmacokinetics/interactions:** Metabolized by CYP3A4 and a P-gp substrate. Strong CYP3A4 inhibitors (azoles, macrolides, grapefruit juice) raise levels, and inducers (rifampin, carbamazepine, phenytoin) lower them. Trough level monitoring is needed for sirolimus.

**Board pearls:** - "Sirolimus = kidney-sparing" (unlike cyclosporine/tacrolimus, which cause nephrotoxicity, hypertension, hyperglycemia, tremor, neurotoxicity). - "Sirolimus = Sir-Limus: Stents, Sparing kidney, Stops IL-2 signaling; side effects: hyperlipidemia, poor wound healing, pancytopenia." - Mechanism difference: sirolimus blocks the IL-2 response (signal 3), whereas CNIs block IL-2 production (signal 1/2 pathway). Antimetabolites (mycophenolate, azathioprine) block lymphocyte proliferation by inhibiting purine synthesis. - A kidney transplant patient on tacrolimus with nephrotoxicity or tremor may be switched to sirolimus.