Journal Article

Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases

Kang, Yun Jee, Claus, Elizabeth B, Ligon, Keith L, Iglehart, J Dirk, Lin, Nancy U, Guo, Hanbing, Xie, Shaozhen, Nguyen, Quang-De, Du, Rose, Alexander, Brian M, Ni, Jing, Hayashi, Marika, Luu, Victor, Ramkissoon, Lori A, Yuan, Guo-Cheng, Marco, Eugenio, Ligon, Azra H, Stover, Daniel G, Goel, Shom, Wang, Zhigang C, Ramkissoon, Shakti H, Winer, Eric P, Zhao, Jean J, Krop, Ian E, Roberts, Thomas M

2016

Overview

In mouse models of patient-derived breast cancer brain metastases, combined inhibition of PI3K and mTOR resulted in regression, and therapeutic response was correlated with a reduction in 4EBP1 phosphorylation. Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/43 / 45/22 / 59/57 / 64/60 / 692/699/67/1059/602 / 692/699/67/1347 / 82/29 / 96/1 / 96/63 / Adaptor Proteins, Signal Transducing / Aminopyridines - pharmacology / Animals / Antineoplastic Agents - pharmacology / Apoptosis - drug effects / Biomedicine / Brain cancer / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Brain Neoplasms - secondary / Brain tumors / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / brief-communication / Cancer Research / Care and treatment / Carrier Proteins - drug effects / Carrier Proteins - metabolism / Caspase 3 - drug effects / Caspase 3 - metabolism / Cell Cycle Proteins / Complications and side effects / Deoxyribonucleic acid / Development and progression / DNA / DNA Repair - genetics / Drug Resistance, Neoplasm - genetics / Drug Therapy, Combination / Eukaryotic Initiation Factors / Everolimus - pharmacology / Female / Gene Expression Profiling / Genetic aspects / Genomic Instability / Health aspects / Humans / Immunohistochemistry / Infectious Diseases / Ki-67 Antigen - drug effects / Ki-67 Antigen - metabolism / Magnetic Resonance Imaging / Mechanistic Target of Rapamycin Complex 1 / Metabolic Diseases / Metastasis / Mice / Mice, SCID / Molecular Medicine / Molecular Targeted Therapy / Morpholines - pharmacology / Multiprotein Complexes - antagonists & inhibitors / Neoplasm Transplantation / Neurosciences / Phosphoinositide-3 Kinase Inhibitors / Phosphoproteins - drug effects / Phosphoproteins - metabolism / Phosphorylation / Phosphotransferases / Receptor, ErbB-2 - metabolism / Remission Induction / Rodents / TOR Serine-Threonine Kinases - antagonists & inhibitors / Xenograft Model Antitumor Assays