MTOR inhibitors

I. Introduction

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in regulating cell growth, proliferation, survival, metabolism, and angiogenesis. mTOR exists in two functionally distinct complexes: mTORC1 and mTORC2. The mTOR inhibitors, also known as rapalogs, selectively inhibit mTORC1. They are primarily used in the management of certain cancers, organ transplantation, and rare genetic disorders such as tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM).

This drug class is part of the broader category of targeted therapies and immunosuppressants, with applications spanning oncology, nephrology, and dermatology.

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II. Mechanism of Action

mTOR inhibitors act by binding to the intracellular protein FKBP12 (FK506-binding protein 12). The resulting FKBP12-rapamycin complex then inhibits the mTORC1 complex by binding directly to the mTOR catalytic subunit.

mTORC1 inhibition leads to:

• Inhibition of protein synthesis via S6K1 and 4E-BP1 modulation

• Blockade of cell cycle progression from G1 to S phase

• Inhibition of angiogenesis via downregulation of HIF-1α

• Decreased lipid and nucleotide synthesis

• Suppression of T-cell activation and proliferation

mTORC2 is not directly inhibited by classic rapalogs but may be affected indirectly through long-term exposure.

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III. Classification of mTOR Inhibitors

1. Rapamycin Derivatives (Rapalogs)

These are analogs of sirolimus (rapamycin) and selectively inhibit mTORC1.

• Sirolimus (Rapamune)

• Everolimus (Afinitor, Zortress)

• Temsirolimus (Torisel)

• Ridaforolimus (investigational in some countries)

2. Next-Generation mTOR Inhibitors

These agents are in development or early clinical use. They may dual-target mTORC1 and mTORC2.

• Vistusertib

• Sapanisertib

• OSI-027

• MLN0128

These are not yet widely available or approved in all jurisdictions.

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IV. Therapeutic Indications

A. Oncology

1. Renal Cell Carcinoma (RCC)

   • Everolimus and temsirolimus are used for advanced RCC after failure of VEGF-targeted therapy.

2. Hormone Receptor–Positive, HER2-Negative Breast Cancer

   • Everolimus is combined with exemestane in postmenopausal women.

3. Neuroendocrine Tumors (NETs)

   • Everolimus is approved for pancreatic, gastrointestinal, or lung NETs.

4. Tuberous Sclerosis–Associated Tumors

   • Everolimus is used in subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma.

5. Lymphangioleiomyomatosis (LAM)

   • Everolimus for progressive disease.

B. Transplantation (Immunosuppression)

• Sirolimus and everolimus are used to prevent organ rejection post kidney and liver transplantation.

• Used in combination with calcineurin inhibitors (e.g., tacrolimus, cyclosporine).

C. Dermatology/Genetics

• Tuberous Sclerosis Complex (TSC): Everolimus is approved for TSC-related SEGA and angiomyolipoma.

• Lymphangioleiomyomatosis (LAM): Approved for lung function preservation in LAM.

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V. Pharmacokinetics

Property	Sirolimus	Everolimus	Temsirolimus
Administration	Oral	Oral	IV
Bioavailability	~15%	~30%	N/A (IV only)
Half-life	~60 hours	~30 hours	Temsirolimus ~17 hrs (metabolized to sirolimus)
Protein Binding	>90%	~74%	>85%
Metabolism	CYP3A4, P-gp	CYP3A4, P-gp	CYP3A4
Elimination	Feces >90%	Feces	Feces

VI. Dosage Guidelines

Sirolimus

• Transplantation: 2–5 mg orally once daily, adjusted to target trough levels.

• Therapeutic range: 5–15 ng/mL

Everolimus

• Transplant: 0.75 mg twice daily (with cyclosporine)

• Oncology: 10 mg once daily

• TSC: Start at 4.5–7.5 mg/m² once daily; titrate to trough level 5–15 ng/mL

Temsirolimus

• Advanced RCC: 25 mg IV once weekly

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VII. Adverse Effects

System Affected	Common Adverse Effects
Hematologic	Anemia, thrombocytopenia, leukopenia
Metabolic	Hyperlipidemia, hyperglycemia, hypertriglyceridemia
Gastrointestinal	Stomatitis, mucositis, diarrhea
Dermatologic	Rash, acneiform eruption, pruritus
Pulmonary	Non-infectious pneumonitis (especially everolimus)
Renal	Proteinuria, increased serum creatinine
Infection Risk	Opportunistic infections (fungal, viral)
Reproductive	Menstrual irregularities, infertility
Other	Delayed wound healing, lymphocele

VIII. Drug Interactions

Interacting Agent	Effect
CYP3A4 Inhibitors	↑ Levels (e.g., ketoconazole, clarithromycin, ritonavir)
CYP3A4 Inducers	↓ Levels (e.g., rifampin, phenytoin, carbamazepine)
P-gp Inhibitors	↑ Absorption of everolimus and sirolimus
Calcineurin Inhibitors	↑ Nephrotoxicity when combined
Grapefruit juice	Avoid (CYP3A4 inhibition)
Live Vaccines	Avoid use during therapy

IX. Monitoring Parameters

1. Trough Drug Levels (especially in transplant and TSC)

2. Complete Blood Count (CBC)

3. Renal function – Creatinine, BUN

4. Liver function tests (LFTs)

5. Fasting Lipid Profile – Monitor for hyperlipidemia

6. Glucose levels – For hyperglycemia or new-onset diabetes

7. Pulmonary symptoms – Monitor for interstitial pneumonitis

8. Mouth ulcers/stomatitis – Common early side effect

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X. Special Populations

• Pregnancy: Category C; avoid unless absolutely necessary

• Lactation: Not recommended during breastfeeding

• Pediatrics: Approved for TSC-related conditions (e.g., SEGA)

• Geriatrics: Use with caution; increased risk of infections

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XI. Resistance Mechanisms

In oncology, resistance to mTOR inhibitors may result from:

• Activation of upstream PI3K/AKT signaling

• Compensatory activation of mTORC2

• Genetic mutations (e.g., in PTEN, TSC1/2)

This has led to the development of dual PI3K/mTOR inhibitors and second-generation mTOR inhibitors.

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XII. Novel Agents and Future Directions

1. Dual mTORC1/mTORC2 Inhibitors: Improve antitumor efficacy (e.g., sapanisertib, vistusertib)

2. Dual PI3K/mTOR Inhibitors: Target multiple nodes of the PI3K/AKT/mTOR pathway

3. Nanoparticle delivery systems: Under investigation to reduce toxicity

4. Combination Therapy: mTOR inhibitors with anti-VEGF, immunotherapies, or hormonal therapies

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XIII. Representative Brand Names

Generic Name	Brand Name(s)
Sirolimus	Rapamune
Everolimus	Afinitor, Zortress
Temsirolimus	Torisel
Ridaforolimus	AP23573 (investigational)

XIV. Contraindications

• Hypersensitivity to any component of the drug

• Uncontrolled infections

• Severe hepatic impairment (dose adjustment required)

• Recent live vaccinations

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XV. Clinical Guidelines and Approvals

• FDA Approvals:

  • Everolimus: RCC, breast cancer, NETs, TSC, LAM

  • Temsirolimus: RCC

  • Sirolimus: Renal transplant immunosuppression

• NCCN Guidelines:

  • Recommend everolimus for second-line RCC and hormone receptor–positive breast cancer

• ESMO Guidelines:

  • Support use in neuroendocrine tumors, TSC, and LAM