Rapamycin

What it is

• Natural macrolide compound discovered from Streptomyces hygroscopicus (found in soil of Rapa Nui → “rapamycin”).
• Prototype mTOR inhibitor (rapalog).
• FDA-approved mainly as an immunosuppressant in solid organ transplantation (not primarily for oncology).

Mechanism of Action

• Binds to FKBP12 → complex inhibits mTORC1 (mammalian target of rapamycin complex 1).
• Results in:
  • ↓ protein synthesis
  • ↓ cell cycle progression (G1 arrest)
  • ↓ angiogenesis
  • ↓ lymphocyte proliferation → immunosuppression

Oncology Relevance

• Rapamycin itself: not widely used in oncology due to poor solubility and PK limitations.
• Led to development of analogs (rapalogs):
  • Temsirolimus (IV)
  • Everolimus (oral)
• These are more clinically useful in renal cell carcinoma, breast cancer, pancreatic NETs, SEGA, tuberous sclerosis–associated tumors.

Toxicities

Similar to other mTOR inhibitors:

• Mucositis/stomatitis
• Hyperlipidemia, hypertriglyceridemia, hyperglycemia
• Myelosuppression
• Delayed wound healing
• Interstitial pneumonitis (non-infectious)
• Infections (immunosuppression)

Pharmacist Pearls

• Metabolized by CYP3A4 & P-gp → watch for drug–drug interactions (azole antifungals, macrolides, rifampin, etc.).
• Monitor: CBC, lipid profile, renal/hepatic function, glucose.
• Counseling: oral ulcers, infection risk, wound healing delay.

Key Point for Oncology: Rapamycin itself is a prototype; temsirolimus & everolimus are the oncology-relevant rapalogs.