Targeting PI3K/mTOR overcomes resistance to HER2-targeted therapy independent of feedback activation of AKT.

Abstract

PURPOSE:

Altered PI3K/mTOR signaling is implicated in the pathogenesis of a number of breast cancers, including those resistant to hormonal and HER2-targeted therapies.

EXPERIMENTAL DESIGN:

The activity of four classes of PI3K/mTOR inhibitory molecules, including a pan-PI3K inhibitor (NVP-BKM120), a p110α isoform-specific PI3K inhibitor (NVP-BYL719), an mTORC1-specific inhibitor (NVP-RAD001), and a dual PI3K/mTORC1/2 inhibitor (NVP-BEZ235), was evaluated both in vitro and in vivo against a panel of 48 human breast cell lines.

RESULTS:

Each agent showed significant antiproliferative activity in vitro, particularly in luminal estrogen receptor-positive and/or HER2(+) cell lines harboring PI3K mutations. In addition, monotherapy with each of the four inhibitors led to significant inhibition of in vivo growth in HER2(+) breast cancer models. The PI3K/mTOR pathway inhibitors were also effective in overcoming both de novo and acquired trastuzumab resistance in vitro and in vivo. Furthermore, combined targeting of HER2 and PI3K/mTOR leads to increased apoptosis in vitro and induction of tumor regression in trastuzumab-resistant xenograft models. Finally, as previously shown, targeting mTORC1 alone with RAD001 leads to consistent feedback activation of AKT both in vitro and in vivo, whereas the dual mTOR1-2/PI3K inhibitor BEZ235 eliminates this feedback loop. However, despite these important signaling differences, both molecules are equally effective in inhibiting tumor cell proliferation both in vitro and in vivo.

CONCLUSION:

These preclinical data support the findings of the BOLERO 3 trial that shows that targeting of the PI3K/mTOR pathway in combination with trastuzumab is beneficial in trastuzumab-resistant breast cancer.

• Authors: Neil A O'Brien, Karen McDonald, Luo Tong, Erika von Euw, Ondrej Kalous, Dylan Conklin, Sara A Hurvitz, Emmanuelle di Tomaso, Christian Schnell, Ronald Linnartz, Richard S Finn, Samit Hirawat, Dennis J Slamon
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 13 Pg. 3507-20 (Jul 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24879796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Trastuzumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, mortality)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm
• Female
• Humans
• Mice
• Molecular Targeted Therapy
• Mutation
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Trastuzumab
• Xenograft Model Antitumor Assays