IL-8 secreted by tumor associated macrophages contribute to lapatinib resistance in HER2-positive locally advanced breast cancer via activation of Src/STAT3/ERK1/2-mediated EGFR signaling
IL-8 secreted by tumor associated macrophages contribute to lapatinib resistance in HER2-positive locally advanced breast cancer via activation of Src/STAT3/ERK1/2-mediated EGFR signaling
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DOI：
10.1016/j.bbamcr.2021.118995
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发表时间：
2021-03-08
影响因子：
5.1
通讯作者：
Mohamed, Mona Mostafa
中科院分区：
文献类型：
--
作者：
Ahmed, Shaza;Mohamed, Hossam Taha;Mohamed, Mona Mostafa
局部晚期乳腺癌(LABC)是一种侵袭性疾病，具有临床表现晚、肿瘤体积大、耐药、生存率低等特点。在LABC中EGFR/HER2的表达和细胞内酪氨酸激酶结构域的激活与预后不良有关。因此，靶向治疗，如抗受体酪氨酸激酶的拉帕替尼药物，在过去十年中得到了更多的发展。对拉帕替尼的反应包括抑制RTK和随后已知也被肿瘤微环境(TME)中的细胞因子激活的信号分子，如Src/STAT3/ERK1/2。本研究的目的是确定可能导致EGFR+/HER2+LABC患者对拉帕替尼耐药的主要细胞因子。事实上，肿瘤相关巨噬细胞(TAM)是TME中细胞因子的主要来源。在此，我们在改良根治术(MRM)中从LABC中分离出TAMs。LABC患者TAMS的细胞因子谱显示IL-8是最显著的高分泌细胞因子。利用体外细胞培养模型，我们发现重组IL-8(50和100 ng/mL)在不同的时间间隔通过激活Src/EGFR和已知在治疗过程中被抑制的信号分子来干扰拉帕替尼的作用。我们建议，为了改善LABC患者对拉帕替尼治疗的反应，最好使用中和或阻断IL-8作用的联合治疗。
Locally advanced breast cancer (LABC) is an aggressive disease characterized by late clinical presentation, large tumor size, treatment resistance and low survival rate. Expression of EGFR/HER2 and activation of intracellular tyrosine kinase domains in LABC are associated with poor prognosis. Thus, target therapies such as the anti-receptor tyrosine kinases lapatinib drug have been more developed in the past decade. The response to lapatinib involves the inhibition of RTKs and subsequently signaling molecules such as Src/STAT3/Erk1/2 known also to be activated by the cytokines in the tumor microenvironment (TME). The aim of the present study is to identify the major cytokine that might contribute to lapatinib resistance in EGFR+/HER2+ LABC patients. Indeed, tumor associated macrophages (TAMs) are the main source of cytokines in the TME. Herein, we isolated TAMs from LABC during modified radical mastectomy (MRM). Cytokine profile of TAMs revealed that IL-8 is the most prominent highly secreted cytokine by TAMs of LABC patients. Using in-vitro cell culture model we showed that recombinant IL-8 (50 and 100 ng/mL) at different time intervals interfere with lapatinib action via activation of Src/EGFR and signaling molecules known to be inhibited during treatment. We proposed that to improve LABC patients' response to lapatinib treatment it is preferred to use combined therapy that neutralize or block the action of IL-8.