脑微环境通过HER3激活介导管腔型乳腺癌对PI3K抑制的抗性。
The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation.
作者信息
Kodack David P, Askoxylakis Vasileios, Ferraro Gino B, Sheng Qing, Badeaux Mark, Goel Shom, Qi Xiaolong, Shankaraiah Ram, Cao Z Alexander, Ramjiawan Rakesh R, Bezwada Divya, Patel Bhushankumar, Song Yongchul, Costa Carlotta, Naxerova Kamila, Wong Christina S F, Kloepper Jonas, Das Rita, Tam Angela, Tanboon Jantima, Duda Dan G, Miller C Ryan, Siegel Marni B, Anders Carey K, Sanders Melinda, Estrada Monica V, Schlegel Robert, Arteaga Carlos L, Brachtel Elena, Huang Alan, Fukumura Dai, Engelman Jeffrey A, Jain Rakesh K
机构信息
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.
Oncology Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
出版信息
Sci Transl Med. 2017 May 24;9(391). doi: 10.1126/scitranslmed.aal4682.
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 -amplified and/or -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 -amplified and/or -mutant breast cancer brain metastases.
尽管靶向治疗通常在全身有效，但它们无法充分控制脑转移瘤。在能够如实地重现这些微环境中不同临床反应的乳腺癌临床前模型中，我们观察到，尽管药物在脑病变中蓄积，但脑转移瘤可逃避磷脂酰肌醇3激酶（PI3K）抑制作用。与颅外疾病相比，我们观察到脑病变中HER3表达和磷酸化增加。HER3阻断克服了扩增和/或突变的乳腺癌脑转移瘤对PI3K抑制剂的耐药性，导致肿瘤生长明显延迟并改善了小鼠存活情况。这些数据为脑微环境中的治疗耐药性提供了机制基础，并确定了针对扩增和/或突变的乳腺癌脑转移瘤的可转化治疗策略。
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