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The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation.
Kodack, David P; Askoxylakis, Vasileios; Ferraro, Gino B; Sheng, Qing; Badeaux, Mark; Goel, Shom; Qi, Xiaolong; Shankaraiah, Ram; Cao, Z Alexander; Ramjiawan, Rakesh R; Bezwada, Divya; Patel, Bhushankumar; Song, Yongchul; Costa, Carlotta; Naxerova, Kamila; Wong, Christina S F; Kloepper, Jonas; Das, Rita; Tam, Angela; Tanboon, Jantima; Duda, Dan G; Miller, C Ryan; Siegel, Marni B; Anders, Carey K; Sanders, Melinda; Estrada, Monica V; Schlegel, Robert; Arteaga, Carlos L; Brachtel, Elena; Huang, Alan; Fukumura, Dai; Engelman, Jeffrey A; Jain, Rakesh K.
Afiliação
  • Kodack DP; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Askoxylakis V; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Ferraro GB; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Sheng Q; Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
  • Badeaux M; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Goel S; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Qi X; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Shankaraiah R; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Cao ZA; Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
  • Ramjiawan RR; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Bezwada D; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Patel B; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Song Y; Department of Medicine, MGH Cancer Center and HMS, Boston, MA 02129, USA.
  • Costa C; Department of Medicine, MGH Cancer Center and HMS, Boston, MA 02129, USA.
  • Naxerova K; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Wong CSF; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Kloepper J; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Das R; Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
  • Tam A; Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
  • Tanboon J; Department of Pathology, MGH and HMS, Boston, MA 02114, USA.
  • Duda DG; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Miller CR; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27514, USA.
  • Siegel MB; Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
  • Anders CK; Division of Hematology Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA.
  • Sanders M; Department of Pathology, Microbiology, and Immunology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.
  • Estrada MV; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.
  • Schlegel R; Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
  • Arteaga CL; Departments of Medicine and Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.
  • Brachtel E; Department of Pathology, MGH and HMS, Boston, MA 02114, USA.
  • Huang A; Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
  • Fukumura D; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
  • Engelman JA; Department of Medicine, MGH Cancer Center and HMS, Boston, MA 02129, USA. jain@steele.mgh.harvard.edu jeffrey.engelman@novartis.com.
  • Jain RK; Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA. jain@steele.mgh.harvard.edu jeffrey.engelman@novartis.com.
Sci Transl Med ; 9(391)2017 05 24.
Article em En | MEDLINE | ID: mdl-28539475
Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Neoplasias da Mama / Fosfatidilinositol 3-Quinases / Receptor ErbB-3 Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Neoplasias da Mama / Fosfatidilinositol 3-Quinases / Receptor ErbB-3 Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article