Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic signaling networks, is frequently activated in ILC. We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the K14-cre;Cdh1Flox/Flox;Trp53Flox/Flox (KEP) mouse model of metastatic ILC. Inhibition of mTOR signaling blocked the growth of primary KEP tumors as well as the progression of metastatic disease. However, primary tumors and distant metastases eventually acquired resistance after long-term AZD8055 treatment, despite continued effective suppression of mTOR signaling in cancer cells. Interestingly, therapeutic responses were associated with increased expression of genes related to antigen presentation. Consistent with this observation, increased numbers of tumor-infiltrating major histocompatibility complex class II-positive (MHCII+) immune cells were observed in treatment-responsive KEP tumors. Acquisition of treatment resistance was associated with loss of MHCII+ cells and reduced expression of genes related to the adaptive immune system. The therapeutic efficacy of mTOR inhibition was reduced in Rag1-/- mice lacking mature T and B lymphocytes, compared to immunocompetent mice. Furthermore, therapy responsiveness could be partially rescued by transplanting AZD8055-resistant KEP tumors into treatment-naïve immunocompetent hosts. Collectively, these data indicate that the PI3K signaling pathway is an attractive therapeutic target in invasive lobular carcinoma, and that part of the therapeutic effect of mTOR inhibition is mediated by the adaptive immune system.

中文翻译：

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转移性小鼠浸润性小叶癌对mTOR抑制的反应部分由适应性免疫系统介导。

乳腺浸润性小叶癌（ILC）的有效治疗因后期发现，浸润性生长，远处转移以及对化学疗法的反应较差而受到阻碍。磷酸肌醇3-激酶（PI3K）信号传导，一种主要的可药物致癌信号传导网络，经常在ILC中被激活。我们在转移性ILC的K14-cre; Cdh1Flox / Flox; Trp53Flox / Flox（KEP）小鼠模型中研究了对雷帕霉素（mTOR）的哺乳动物靶标抑制剂AZD8055的治疗反应和耐药性。抑制mTOR信号传导可阻断原发性KEP肿瘤的生长以及转移性疾病的进展。然而，尽管继续有效抑制癌细胞中的mTOR信号传导，但经过长期AZD8055治疗后，原发性肿瘤和远处转移最终获得了抵抗。有趣的是 治疗反应与抗原呈递相关基因的表达增加有关。与该观察结果一致，在对治疗有反应的KEP肿瘤中观察到肿瘤浸润的主要组织相容性复合物II类阳性（MHCII +）免疫细胞的数量增加。获得治疗抗性与MHCII +细胞的丢失和与适应性免疫系统有关的基因表达降低有关。与具有免疫功能的小鼠相比，在缺乏成熟的T和B淋巴细胞的Rag1-/-小鼠中mTOR抑制的治疗功效降低。此外，通过将耐AZD8055的KEP肿瘤移植到未接受过免疫治疗的宿主中，可以部分挽救治疗反应性。总的来说，