Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-κB signaling.
Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-κB signaling.
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巨噬细胞通过激活 NF-kappa B 信号传导赋予乳腺癌对 PI3K 抑制剂 GDC-0941 的抗性
DOI：
10.1038/s41419-018-0849-6
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发表时间：
2018-07-24
影响因子：
9
通讯作者：
Luo F
中科院分区：
文献类型：
--
作者：
Usman MW;Gao J;Zheng T;Rui C;Li T;Bian X;Cheng H;Liu P;Luo F
PI 3 K通路是上皮癌中最失调的信号通路之一，并且已经成为活跃的临床前和临床开发下的有吸引力的治疗靶点。然而，最近的临床试验研究表明，在晚期癌症中阻断PI 3 K活性通常会导致耐药性的发展和疾病的复发。已经进行了大量的努力来阐明耐药机制，并确定与PI 3 K抑制剂在实体瘤中的合理药物组合。在当前的研究中，我们发现GDC-0941对PI 3 K的抑制增加了小鼠4 T1乳腺肿瘤模型中巨噬细胞的浸润并诱导了巨噬细胞相关细胞因子和趋化因子的表达。使用体外共培养系统，我们表明巨噬细胞的存在导致4 T1肿瘤细胞中NF-κB信号传导的活化，使得肿瘤细胞对GDC-0941的PI 3 K抑制具有抗性。此外，我们还发现阿司匹林可以阻断PI 3 K抑制诱导的NF-κB信号通路的激活，并且在巨噬细胞存在的体外共培养系统中，GDC-0941和阿司匹林联合使用导致4 T1细胞生长减弱和凋亡增强。一致地，组合治疗还有效地减少体内4 T1乳腺肿瘤模型中的肿瘤负荷、巨噬细胞浸润和肺转移。总之，我们的结果表明微环境中的巨噬细胞可能有助于乳腺癌细胞对PI 3 K抑制的抵抗，并揭示了一种新的组合模式，以提高PI 3 K靶向治疗的疗效。
The PI3K pathway is one of the most dysregulated signaling pathways in epithelial cancers and has become an attractive therapeutic target under active preclinical and clinical development. However, recent clinical trial studies revealed that blockade of PI3K activity in advanced cancer often leads to the development of resistance and relapse of the diseases. Intense efforts have been made to elucidate resistance mechanisms and identify rational drug combinations with PI3K inhibitors in solid tumors. In the current study, we found that PI3K inhibition by GDC-0941 increased macrophage infiltration and induced the expression of macrophage-associated cytokines and chemokines in the mouse 4T1 breast tumor model. Using the in vitro co-culture system, we showed that the presence of macrophages led to the activation of NF-κB signaling in 4T1 tumor cells, rendering tumor cells resistant to PI3K inhibition by GDC-0941. Furthermore, we found that Aspirin could block the activation of NF-κB signaling induced by PI3K inhibition, and combined use of GDC-0941 and Aspirin resulted in attenuated cell growth and enhanced apoptosis of 4T1 cells in the in vitro co-culture system with the presence of macrophages. Consistently, the combination treatment also effectively reduced tumor burden, macrophage infiltration and pulmonary metastasis in in vivo 4T1 breast tumor model. Together, our results suggested macrophages in microenvironment may contribute to the resistance of breast cancer cells to PI3K inhibition and reveal a new combination paradigm to improve the efficacy of PI3K-targeted therapy.
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影响因子：
11.2
作者：
Henry WS;Laszewski T;Tsang T;Beca F;Beck AH;McAllister SS;Toker A
通讯作者：
Toker A
影响因子：
3.8
作者：
Kutuk, O;Basaga, H
通讯作者：
Basaga, H
影响因子：
56.9
作者：
KOPP, E;GHOSH, S
通讯作者：
GHOSH, S
影响因子：
50.3
作者：
Ruffell B;Coussens LM
通讯作者：
Coussens LM
影响因子：
28.2
作者：
Smith MP;Sanchez-Laorden B;O'Brien K;Brunton H;Ferguson J;Young H;Dhomen N;Flaherty KT;Frederick DT;Cooper ZA;Wargo JA;Marais R;Wellbrock C
通讯作者：
Wellbrock C