Definition
- PI3K inhibitors target the PI3K/AKT/mTOR signaling pathway, which is often dysregulated in cancers.
- This pathway controls cell growth, proliferation, survival, and metabolism.
- Inhibition leads to cell cycle arrest, apoptosis, and decreased tumor growth.
Therapeutic indications
Key Approved Drugs
| Drug | Isoform Specificity | Route | Indications | Notes / Toxicities |
|---|---|---|---|---|
| Idelalisib | PI3Kδ | Oral | Relapsed CLL, FL, SLL | Hepatotoxicity, diarrhea/colitis, pneumonitis, infections (esp. opportunistic) |
| Copanlisib | PI3Kα/δ | IV | Relapsed FL | Hyperglycemia, hypertension (transient), infusion reactions, infections |
| Duvelisib | PI3Kδ/γ | Oral | Relapsed CLL/SLL, FL | Diarrhea/colitis, infections, neutropenia, rash |
| Alpelisib | PI3Kα | Oral | HR+/HER2- PIK3CA-mutated advanced breast cancer (with fulvestrant) | Hyperglycemia (dose-limiting), rash, diarrhea, hepatotoxicity |
Mechanism of Action
- Inhibits PI3K isoforms → downstream inhibition of AKT and mTOR signaling.
- Reduces cell proliferation and survival, induces apoptosis.
- Particularly effective in cancers with PI3K pathway activation, e.g., PIK3CA mutations, B-cell malignancies.
Toxicities
- Hematologic: neutropenia, thrombocytopenia, anemia (mostly duvelisib, idelalisib).
- Gastrointestinal: diarrhea, colitis (can be severe, immune-mediated).
- Hepatotoxicity: elevated AST/ALT (monitor closely, dose modifications required).
- Infections: bacterial, viral, and opportunistic (PJP, CMV) – prophylaxis often needed.
- Metabolic: hyperglycemia (esp. alpelisib, copanlisib), hypertension (copanlisib).
- Dermatologic: rash, pruritus.
- Rare: pneumonitis, intestinal perforation.
Monitoring
- CBC with differential.
- Liver function tests (AST, ALT, bilirubin).
- Blood glucose (especially with alpelisib or copanlisib).
- Blood pressure (copanlisib).
- Monitor for diarrhea/colitis, infections, and pulmonary symptoms.
Summary
PI3K inhibitors block a key signaling pathway involved in cell survival and proliferation. They are used in B-cell malignancies (idelalisib, duvelisib, copanlisib) and PIK3CA-mutated breast cancer (alpelisib). Main concerns include hepatotoxicity, severe diarrhea/colitis, infections, and metabolic effects.
Synonyms
PI3K Inhibitors, PI3K Inhibitor