Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab.

Abstract

PURPOSE:

Oncogenic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is prevalent in breast cancer and has been associated with resistance to HER2 inhibitors in the clinic. We therefore investigated the combinatorial activity of GDC-0941, a novel class I PI3K inhibitor, with standard-of-care therapies for HER2-amplified breast cancer.

EXPERIMENTAL DESIGN:

Three-dimensional laminin-rich extracellular matrix cultures of human breast cancer cells were utilized to provide a physiologically relevant approach to analyze the efficacy and molecular mechanism of combination therapies ex vivo. Combination studies were done using GDC-0941 with trastuzumab (Herceptin), pertuzumab, lapatinib (Tykerb), and docetaxel, the principal therapeutic agents that are either approved or being evaluated for treatment of early HER2-positive breast cancer.

RESULTS:

Significant GDC-0941 activity (EC(50) <1 micromol/L) was observed for >70% of breast cancer cell lines that were examined in three-dimensional laminin-rich extracellular matrix culture. Differential responsiveness to GDC-0941 as a single agent was observed for luminal breast cancer cells upon stimulation with the HER3 ligand, heregulin. Combined treatment of GDC-0941, trastuzumab, and pertuzumab resulted in growth inhibition, altered acinar morphology, and suppression of AKT mitogen-activated protein kinase (MAPK) / extracellular signed-regulated kinase (ERK) kinase and MEK effector signaling pathways for HER2-amplified cells in both normal and heregulin-supplemented media. The GDC-0941 and lapatinib combination further showed that inhibition of HER2 activity was essential for maximum combinatorial efficacy. PI3K inhibition also rendered HER2-amplified BT-474M1 cells and tumor xenografts more sensitive to docetaxel.

CONCLUSIONS:

GDC-0941 is efficacious in preclinical models of breast cancer. The addition of GDC-0941 to HER2-directed treatment could augment clinical benefit in breast cancer patients.

• Authors: Evelyn Yao, Wei Zhou, Si Tuen Lee-Hoeflich, Tom Truong, Peter M Haverty, Jeffrey Eastham-Anderson, Nicholas Lewin-Koh, Bert Gunter, Marcia Belvin, Lesley J Murray, Lori S Friedman, Mark X Sliwkowski, Klaus P Hoeflich
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 12 Pg. 4147-56 (Jun 15 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19509167 (Publication Type: Journal Article)

Chemical References

• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Enzyme Inhibitors
• Indazoles
• Phosphoinositide-3 Kinase Inhibitors
• Quinazolines
• Sulfonamides
• Taxoids
• Lapatinib
• Docetaxel
• Receptor, ErbB-2
• Receptor, ErbB-3
• pertuzumab
• Trastuzumab

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Breast Neoplasms (drug therapy, enzymology)
• Cell Line, Tumor
• Docetaxel
• Enzyme Inhibitors (therapeutic use)
• Humans
• Indazoles (therapeutic use)
• Lapatinib
• Mice
• Mice, Nude
• Phosphoinositide-3 Kinase Inhibitors
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Receptor, ErbB-3 (antagonists & inhibitors)
• Signal Transduction (drug effects, physiology)
• Sulfonamides (therapeutic use)
• Taxoids (pharmacology)
• Trastuzumab
• Xenograft Model Antitumor Assays