The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation

David P. Kodack; Vasileios Askoxylakis; Gino B. Ferraro; Qing Sheng; Mark Badeaux; Shom Goel; Xiaolong Qi; Ram Shankaraiah; Z. Alexander Cao; Rakesh R. Ramjiawan; Divya Bezwada; Bhushankumar Patel; Yongchul Song; Carlotta Costa; Kamila Naxerova; Christina S. F. Wong; Jonas Kloepper; Rita Das; Angela Tam; Jantima Tanboon; Dan G. Duda; C. Ryan Miller; Marni B. Siegel; Carey K. Anders; Melinda Sanders; Monica V. Estrada; Robert Schlegel; Carlos L. Arteaga; Elena Brachtel; Alan Huang; Dai Fukumura; Jeffrey A. Engelman; Rakesh K. Jain

doi:10.1126/scitranslmed.aal4682

Research ArticleCancer

The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation

David P. Kodack¹,*,
Vasileios Askoxylakis¹,*,
Gino B. Ferraro¹,*,
Qing Sheng²,†,
Mark Badeaux¹,
Shom Goel¹,‡,
Xiaolong Qi¹,§,
Ram Shankaraiah¹,
Z. Alexander Cao²,
Rakesh R. Ramjiawan¹,
Divya Bezwada¹,
Bhushankumar Patel¹,
Yongchul Song³,
Carlotta Costa³,
Kamila Naxerova¹,
Christina S. F. Wong¹,
Jonas Kloepper¹,¶,
Rita Das²,†,
Angela Tam²,†,
Jantima Tanboon⁴,
Dan G. Duda¹,
C. Ryan Miller⁵,
Marni B. Siegel⁶,
Carey K. Anders⁷,
Melinda Sanders⁸,
Monica V. Estrada⁹,
Robert Schlegel²,
Carlos L. Arteaga¹⁰,
Elena Brachtel⁴,
Alan Huang²,
Dai Fukumura¹,
Jeffrey A. Engelman³,||,** and
Rakesh K. Jain¹,**

¹Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
²Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
³Department of Medicine, MGH Cancer Center and HMS, Boston, MA 02129, USA.
⁴Department of Pathology, MGH and HMS, Boston, MA 02114, USA.
⁵Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27514, USA.
⁶Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
⁷Division of Hematology Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA.
⁸Department of Pathology, Microbiology, and Immunology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.
⁹Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.
¹⁰Departments of Medicine and Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.

↵**Corresponding author. Email: jain{at}steele.mgh.harvard.edu (R.K.J.); jeffrey.engelman{at}novartis.com (J.A.E.)

↵* These authors contributed equally to this work.
↵† Present address: Oncology Translational Research, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
↵‡ Present address: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
↵§ Present address: Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
↵¶ Present address: Centre Hospitalier Universitaire Vaudois, Département de Médecine Interne, CHUV-UNIL, Rue du Bugnon 46, 1011 Lausanne, Switzerland.
↵|| Present address: Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

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Science Translational Medicine 24 May 2017:
Vol. 9, Issue 391, eaal4682
DOI: 10.1126/scitranslmed.aal4682

David P. Kodack

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Vasileios Askoxylakis

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Gino B. Ferraro

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Qing Sheng

Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

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Mark Badeaux

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Shom Goel

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Xiaolong Qi

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Ram Shankaraiah

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Z. Alexander Cao

Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

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Rakesh R. Ramjiawan

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Divya Bezwada

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Bhushankumar Patel

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Yongchul Song

Department of Medicine, MGH Cancer Center and HMS, Boston, MA 02129, USA.

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Carlotta Costa

Department of Medicine, MGH Cancer Center and HMS, Boston, MA 02129, USA.

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Kamila Naxerova

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Christina S. F. Wong

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Jonas Kloepper

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Rita Das

Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

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Angela Tam

Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

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Jantima Tanboon

Department of Pathology, MGH and HMS, Boston, MA 02114, USA.

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Dan G. Duda

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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C. Ryan Miller

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27514, USA.

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Marni B. Siegel

Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.

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Carey K. Anders

Division of Hematology Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA.

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Melinda Sanders

Department of Pathology, Microbiology, and Immunology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.

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Monica V. Estrada

Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.

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Robert Schlegel

Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

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Carlos L. Arteaga

Departments of Medicine and Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37203, USA.

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Elena Brachtel

Department of Pathology, MGH and HMS, Boston, MA 02114, USA.

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Alan Huang

Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

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Dai Fukumura

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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Jeffrey A. Engelman

Department of Medicine, MGH Cancer Center and HMS, Boston, MA 02129, USA.

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For correspondence: jain@steele.mgh.harvard.edu jeffrey.engelman@novartis.com

Rakesh K. Jain

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

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For correspondence: jain@steele.mgh.harvard.edu jeffrey.engelman@novartis.com

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The brain microenvironment triggers HER3-dependent de novo resistance to therapies targeting PI3K or HER2 in HER2-positive and/or PIK3CA-mutant breast cancer cells.

The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation

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