@article{bd7dd83e4a4f49c59dd7f893319e7e15,
title = "The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation",
abstract = "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 PIK3CAmutant breast cancer brain metastases.",
author = "Kodack, {David P.} and Vasileios Askoxylakis and Ferraro, {Gino B.} and Qing Sheng and Mark Badeaux and Shom Goel and Xiaolong Qi and Ram Shankaraiah and Cao, {Z. Alexander} and Ramjiawan, {Rakesh R.} and Divya Bezwada and Bhushankumar Patel and Yongchul Song and Carlotta Costa and Kamila Naxerova and Wong, {Christina S.F.} and Jonas Kloepper and Rita Das and Angela Tam and Jantima Tanboon and Duda, {Dan G.} and Ryan Miller and Siegel, {Marni B.} and Anders, {Carey K.} and Melinda Sanders and Estrada, {Monica V.} and Robert Schlege and Arteaga, {Carlos L.} and Elena Brachtel and Alan Huang and Dai Fukumura and Engelman, {Jeffrey A.} and Jain, {Rakesh K.}",
note = "Funding Information: Supported in part by the U.S. Department of Defense Breast Cancer Research Innovator Award W81XWH-10-1-0016 (to R.K.J.); the U.S. National Cancer Institute grants R01-CA126642 and R35-CA197743 (to R.K.J.), P01-CA080124 (to R.K.J. and D.F.), R01-CA096915 (to D.F.), and Breast SPORE grant P50 CA098131 (to C.L.A.); the Ludwig Center at Harvard (to R.K.J.); National Foundation for Cancer Research (NFCR) (R.K.J.); the MIT-HCC (Massachusetts Institute of Technology-Harvard Cancer Center) Bridge grant (to R.K.J.); the Federal Share Proton Beam Program Income (to R.K.J.); grant T32-CA073479 (to D.P.K.); the NIH/National Cancer Institute grant R01CA137008 (to J.A.E.); the German Research Foundation grant (Deutsche Forschungsgemeinschaft) AS 422-2/1 (to V.A.); and the Susan G. Komen for the Cure (GBF) and Dutch Cancer Society Grant Trustees (KWF Stagebeurs Buitenland) (to R.R.R). M.B.S. is supported by the National Cancer Institute F30-CA200345. Publisher Copyright: {\textcopyright} The Authors, some rights reserved;.",
year = "2017",
month = may,
day = "24",
doi = "10.1126/scitranslmed.aal4682",
language = "English (US)",
volume = "9",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "391",
}