使用小分子化合物靶向 SOST 可延缓乳腺癌骨转移,Molecular Cancer

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使用小分子化合物靶向 SOST 可延缓乳腺癌骨转移
Molecular Cancer ( IF 27.7 ) Pub Date : 2022-12-29 , DOI: 10.1186/s12943-022-01697-4
Lisha Sun ₁ , Yixiao Zhang _{1,

2} , Guanglei Chen ₁ , Yaoting Ji ₃ , Qingtian Ma ₁ , Xinbo Qiao ₁ , Sijin Wu ₄ , Lin Zhou ₅ , Jiawen Bu ₁ , Xudong Zhu ₁ , Xiaoying Zhang ₁ , Xiaofan Jiang ₁ , Chao Liu ₁ , Xinnan Li ₁ , Yang Liu ₅ , Yongliang Yang ₆ , Caigang Liu ₁

Affiliation

骨质疏松症会加剧乳腺癌向骨骼的转移，与长期生存率差相关，并且治疗选择有限。硬化蛋白 (SOST) 是骨形成的内源性抑制剂，是治疗骨质疏松症的一个有吸引力的靶点。然而，SOST是否可以作为乳腺癌骨转移的治疗靶点，靶向乳腺癌细胞内SOST的小分子化合物是否可以抑制乳腺癌骨转移尚不清楚。442 个乳腺癌组织中的 SOST 表达通过免疫组织化学表征，并统计分析与乳腺癌骨转移的关联。诱导骨转移性乳腺癌 SCP2 细胞进行 SOST 沉默或过表达，并在体外和体内测试其骨转移行为。为了确定潜在的治疗方法，我们从一个小化学分子库中筛选了 SOST 与 STAT3 相互作用的抑制剂，并测试了一种抑制剂在体外和体内对乳腺癌生长和骨转移的抑制作用。我们发现上调的 SOST 表达与乳腺癌骨转移和乳腺癌患者的较差生存有关。SOST 沉默显着降低了 SCP2 细胞的骨转移能力。SOST 与 STAT3 相互作用以增强 TGF-β/KRAS 信号传导，从而增加肿瘤生长和骨转移。用一种先导候选药物 S6 治疗可显着抑制小鼠乳腺癌类器官的生长和骨转移。我们的研究结果突出了一类新的治疗乳腺癌骨转移的潜在疗法。我们从化学小分子库中筛选出 SOST 与 STAT3 相互作用的抑制剂，并在体外和体内测试了一种抑制剂对乳腺癌生长和骨转移的抑制作用。我们发现上调的 SOST 表达与乳腺癌骨转移和乳腺癌患者的较差生存有关。SOST 沉默显着降低了 SCP2 细胞的骨转移能力。SOST 与 STAT3 相互作用以增强 TGF-β/KRAS 信号传导，从而增加肿瘤生长和骨转移。用一种先导候选药物 S6 治疗可显着抑制小鼠乳腺癌类器官的生长和骨转移。我们的研究结果突出了一类新的治疗乳腺癌骨转移的潜在疗法。我们从化学小分子库中筛选出 SOST 与 STAT3 相互作用的抑制剂，并在体外和体内测试了一种抑制剂对乳腺癌生长和骨转移的抑制作用。我们发现上调的 SOST 表达与乳腺癌骨转移和乳腺癌患者的较差生存有关。SOST 沉默显着降低了 SCP2 细胞的骨转移能力。SOST 与 STAT3 相互作用以增强 TGF-β/KRAS 信号传导，从而增加肿瘤生长和骨转移。用一种先导候选药物 S6 治疗可显着抑制小鼠乳腺癌类器官的生长和骨转移。我们的研究结果突出了一类新的治疗乳腺癌骨转移的潜在疗法。

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Targeting SOST using a small-molecule compound retards breast cancer bone metastasis

Breast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis. SOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo. We found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-β/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice. Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

更新日期：2022-12-29

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