| Literature DB >> 28539475 |
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 Engelman11, Rakesh K Jain12.
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 PIK3CA-mutant breast cancer brain metastases.Entities:
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Year: 2017 PMID： 28539475 PMCID： PMC5917603 DOI： 10.1126/scitranslmed.aal4682
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956