Combination Inhibition of PI3K and MTORC1 Yields Durable Remissions in Mice Bearing Orthotopic Patient-derived Xenografts of HER2-positive Breast Cancer Brain Metastases

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2016 Jun 9

PMID 27270588

Citations 68

Authors

Jing Ni

Shakti H Ramkissoon

Shaozhen Xie

Shom Goel

Daniel G Stover

Hanbing Guo

Victor Luu

Eugenio Marco

Lori A Ramkissoon

Yun Jee Kang

Marika Hayashi

Quang-De Nguyen

Azra H Ligon

Rose Du

Elizabeth B Claus

Brian M Alexander

Guo-Cheng Yuan

Zhigang C Wang

J Dirk Iglehart

Ian E Krop

Thomas M Roberts

Eric P Winer

Nancy U Lin

Keith L Ligon

Jean J Zhao

Affiliations

Soon will be listed here.

Abstract

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.

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