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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
PTEN-deficient cancers depend on PIK3CB
Susan Wee1, Dmitri Wiederschain, Sauveur-Michel Maira
1Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Summary
PTEN-deficient cancers rely on PIK3CB (p110beta) signaling, not PIK3CA (p110alpha), for growth. Targeting PIK3CB is crucial for treating these specific tumors, highlighting the need for tailored PI3K pathway therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Deregulation of the PI3K/AKT pathway is common in human cancers.
- This deregulation frequently occurs via PTEN loss or PIK3CA mutations.
- PIK3CA-mutant tumors depend on p110alpha activity, but PTEN-deficient tumors' reliance on PI3K isoforms was unclear.
Purpose of the Study:
- To identify the critical PI3K isoforms driving proliferation in PTEN-deficient cancers.
- To investigate the role of PIK3CA and PIK3CB in tumor growth.
- To determine if PIK3CB lipid kinase activity is essential for PTEN-deficient tumor survival.
Main Methods:
- Utilized a lentiviral inducible shRNA system for selective PI3K isoform inactivation (PIK3CA, PIK3CB, PIK3CD).
- Assessed downstream PI3K signaling and cell growth in colorectal cancer cell lines.
- Evaluated the effects of PIK3CB down-regulation in both cell-based and in vivo models.
Main Results:
- PIK3CA down-regulation inhibited growth in PIK3CA-mutant cells but not in PTEN-deficient cells.
- PIK3CB inactivation led to PI3K pathway shutdown and growth inhibition in PTEN-deficient cancer cell lines.
- PIK3CB's essential role in PTEN-deficient cancers was dependent on its lipid kinase activity.
Conclusions:
- PTEN-deficient tumors depend on PIK3CB (p110beta) signaling, unlike PIK3CA-mutant tumors that require PIK3CA (p110alpha).
- Therapeutic strategies must consider the specific genetic alterations driving PI3K pathway activation.
- Targeting PIK3CB offers a potential therapeutic avenue for PTEN-deficient cancers.
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