More antitumor efficacy of the PI3K inhibitor GDC-0941 in breast cancer with PIK3CA mutation or HER2 amplification status in vitro.

Abstract

PIK3CA is probably the most commonly mutated kinase in several malignant tumors. Activation of class I phosphatidylinositol 3' kinase (PI3K) regulates tumor proliferation, survival, etc. This study sought to identify whether the pan-inhibitor has more antitumor efficacy in breast cancer cells with PIK3CA Mutation or HER2 amplification than basal-like cancer cells. The proliferation of breast cancer cells was measured by MTT assay in the presence of GDC-0941. Afterwards, we determined the visible changes in signaling in the PI3K/AKT/mTOR pathway. Finally, we examined GDC-0941 effects on cell cycle, apoptosis and motility. GDC-0941 exhibited excellent inhibition on three cell lines with PIK3CA mutation or HER2 amplification. In addition, GDC-0941 resulted in decreased Akt activity. GDC-0941 downregulated the key components of the cell cycle machinery, such as cyclin D1, upregulated the apoptotic markers and inhibited cell motility on three cell lines with PIK3CA Mutation or HER2 amplification. Antitumor activity of GDC-0941 treatment amongst tumor cell lines with PIK3CA mutation and HER2 amplification may have clinical utility in patients with these oncogenic alterations.

• Authors: Jie Zheng, Huan Wang, Jia Yao, Xianjin Zou
• Journal: Die Pharmazie (Pharmazie) Vol. 69 Issue 1 Pg. 38-42 (Jan 2014) ISSN: 0031-7144 [Print] Germany
• PMID: 24601221 (Publication Type: Journal Article)

Chemical References

• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• Apoptosis Regulatory Proteins
• Cell Cycle Proteins
• Indazoles
• Indicators and Reagents
• Phosphoinositide-3 Kinase Inhibitors
• Sulfonamides
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Blotting, Western
• Breast Neoplasms (drug therapy)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Class I Phosphatidylinositol 3-Kinases
• Female
• Humans
• Indazoles (pharmacology)
• Indicators and Reagents
• Mutation (physiology)
• Phosphatidylinositol 3-Kinases (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Receptor, ErbB-2 (genetics)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Wound Healing (drug effects)