PT  - JOURNAL ARTICLE
AU  - Kodack, David P.
AU  - Askoxylakis, Vasileios
AU  - Ferraro, Gino B.
AU  - Sheng, Qing
AU  - Badeaux, Mark
AU  - Goel, Shom
AU  - Qi, Xiaolong
AU  - Shankaraiah, Ram
AU  - Cao, Z. Alexander
AU  - Ramjiawan, Rakesh R.
AU  - Bezwada, Divya
AU  - Patel, Bhushankumar
AU  - Song, Yongchul
AU  - Costa, Carlotta
AU  - Naxerova, Kamila
AU  - Wong, Christina S. F.
AU  - Kloepper, Jonas
AU  - Das, Rita
AU  - Tam, Angela
AU  - Tanboon, Jantima
AU  - Duda, Dan G.
AU  - Miller, C. Ryan
AU  - Siegel, Marni B.
AU  - Anders, Carey K.
AU  - Sanders, Melinda
AU  - Estrada, Monica V.
AU  - Schlegel, Robert
AU  - Arteaga, Carlos L.
AU  - Brachtel, Elena
AU  - Huang, Alan
AU  - Fukumura, Dai
AU  - Engelman, Jeffrey A.
AU  - Jain, Rakesh K.
TI  - The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation
AID  - 10.1126/scitranslmed.aal4682
DP  - 2017 May 24
TA  - Science Translational Medicine
PG  - eaal4682
VI  - 9
IP  - 391
4099  - http://stm.sciencemag.org/content/9/391/eaal4682.short
4100  - http://stm.sciencemag.org/content/9/391/eaal4682.full
AB  - Although targeted therapies for cancer offer great promise, they are often much less effective against brain metastases than against peripheral tumors. This is generally attributed to the drugs’ difficulty in penetrating the blood-brain barrier, but Kodack et al. now demonstrate that this is not the only reason. The authors discovered that, at least in breast cancer, the brain microenvironment itself plays a role in treatment resistance in metastatic tumors. Using mouse models and human cancer samples, the researchers found increased expression of human epidermal growth factor receptor 3 (HER3) in breast cancer–associated brain lesions and showed that it facilitates the tumors’ survival in the presence of targeted treatment and that inhibiting can help overcome resistance to therapy.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.