Modeling anti-IL-6 therapy using breast cancer patient-derived xenografts.
The pleiotropic cytokine IL-6 accelerates the progression of breast cancer in a variety of preclinical models through the activation of the STAT3 (signal transducer and activator of transcription 3) signaling pathway. However, the proportion of breast cancers sensitive to anti-IL-6 therapies is not known. This study evaluates the efficacy of anti-IL-6 therapies using breast cancer patient derived xenografts (PDXs). During the generation of our collection of PDXs, we showed that the successful engraftment of tumor tissue in immunodeficient mice correlates with bad prognosis. Four PDXs out of six were resistant to anti-IL-6 therapies and the expression of IL-6, its receptor or the levels of phospho-STAT3 (the active form of the signal transducer) did not correlate with sensitivity. Using cell cultures established from the PDXs as well as samples from in vivo treatments, we showed that only tumors in which the activation of STAT3 depends on IL-6 respond to the blocking antibodies. Our results indicate that only a fraction of breast tumors are responsive to anti-IL-6 therapies. In order to identify responsive tumors, a functional assay to determine the dependence of STAT3 activation on IL-6 should be performed.
Preclinical and Clinical Research Programs, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Beatriz
B
Morancho
Preclinical and Clinical Research Programs, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Mariano
M
Zacarías-Fluck
Breast Surgical Unit, Breast Cancer Center, Hospital Universitario Vall d´Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Antonio
A
Esgueva
Preclinical and Clinical Research Programs, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Cristina
C
Bernadó-Morales
Division of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Serena
S
Di Cosimo
Preclinical and Clinical Research Programs, Vall d'Hebron Institute of Oncology, Barcelona, Spain.|Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain.|Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.
Aleix
A
Prat
Preclinical and Clinical Research Programs, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Javier
J
Cortés
Preclinical and Clinical Research Programs, Vall d'Hebron Institute of Oncology, Barcelona, Spain.|Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain.|Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
Joaquín
J
Arribas
Breast Surgical Unit, Breast Cancer Center, Hospital Universitario Vall d´Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Isabel T
IT
Rubio
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C504234:siltuximab
IL-6; STAT3; breast cancer; patient-derived xenografts