Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases.
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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Jing
J
Ni
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Shakti H
SH
Ramkissoon
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Shaozhen
S
Xie
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Shom
S
Goel
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Daniel G
DG
Stover
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Hanbing
H
Guo
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Victor
V
Luu
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Eugenio
E
Marco
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Lori A
LA
Ramkissoon
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Yun Jee
YJ
Kang
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Marika
M
Hayashi
Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Quang-De
QD
Nguyen
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Azra H
AH
Ligon
Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Rose
R
Du
Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.|School of Public Health, Yale University, New Haven, Connecticut, USA.
Elizabeth B
EB
Claus
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Brian M
BM
Alexander
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Guo-Cheng
0000-0002-2283-4714
GC
Yuan
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Zhigang C
ZC
Wang
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
J Dirk
JD
Iglehart
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Ian E
IE
Krop
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Thomas M
TM
Roberts
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Eric P
EP
Winer
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Nancy U
NU
Lin
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Keith L
KL
Ligon
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Jean J
JJ
Zhao
D048868:Adaptor Proteins, Signal Transducing; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins; D004260:DNA Repair / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004359:Drug Therapy, Combination; D039642:Eukaryotic Initiation Factors; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012074:Remission Induction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D000631:Aminopyridines; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D053148:Caspase 3; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D000068338:Everolimus; D019394:Ki-67 Antigen; D000076222:Mechanistic Target of Rapamycin Complex 1; D009025:Morpholines; D046912:Multiprotein Complexes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C499527:Eif4ebp1 protein, mouse; C571178:NVP-BKM120; C508053:ERBB2 protein, human; C505409:Casp3 protein, mouse