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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 PIK3CA-mutant breast cancer brain metastases.

SUBMITTER: Kodack DP 

PROVIDER: S-EPMC5917603 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Kodack David P DP   Askoxylakis Vasileios V   Ferraro Gino B GB   Sheng Qing Q   Badeaux Mark M   Goel Shom S   Qi Xiaolong X   Shankaraiah Ram R   Cao Z Alexander ZA   Ramjiawan Rakesh R RR   Bezwada Divya D   Patel Bhushankumar B   Song Yongchul Y   Costa Carlotta C   Naxerova Kamila K   Wong Christina S F CSF   Kloepper Jonas J   Das Rita R   Tam Angela A   Tanboon Jantima J   Duda Dan G DG   Miller C Ryan CR   Siegel Marni B MB   Anders Carey K CK   Sanders Melinda M   Estrada Monica V MV   Schlegel Robert R   Arteaga Carlos L CL   Brachtel Elena E   Huang Alan A   Fukumura Dai D   Engelman Jeffrey A JA   Jain Rakesh K RK  

Science translational medicine 20170501 391

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 bl  ...[more]

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