Simultaneous Inhibition of MEK and Hh Signaling Reduces Pancreatic Cancer Metastasis.
Simultaneous Inhibition of MEK and Hh Signaling Reduces Pancreatic Cancer Metastasis.
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DOI：
10.3390/cancers10110403
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发表时间：
2018-10-26
期刊：
影响因子：
5.2
通讯作者：
Xie J
中科院分区：
文献类型：
--
作者：
Gu D;Lin H;Zhang X;Fan Q;Chen S;Shahda S;Liu Y;Sun J;Xie J
胰腺癌，主要是胰腺导管腺癌（PDAC），是最致命的癌症类型之一，仅在美国，2018年估计就有44，330人死亡。虽然靶向治疗和免疫检查点抑制剂显著改善了肺癌和肾细胞癌患者的治疗选择，但胰腺癌的治疗进展甚微，目前5年生存率仅为8%。在诊断时，大多数胰腺癌病例（约80%）已经转移。因此，确定减少胰腺癌转移的方法是未满足的医疗需求。此外，胰腺癌对化疗有抵抗力是众所周知的。虽然Kirsten RAt肉瘤病毒癌基因（K-RAS）突变是胰腺癌的主要驱动因素，但RAS信号传导的特异性抑制一直非常具有挑战性，联合治疗被认为是有希望的。在这项研究中，我们报告了刺猬（Hh）和促分裂原活化蛋白/细胞外信号调节激酶激酶（MEK）信号抑制剂的组合减少了小鼠模型中的胰腺癌转移。在使用人胰腺癌细胞的胰腺癌转移小鼠模型中，我们发现Hh靶基因Gli1在胰腺癌转移期间上调。smoothened信号的特异性抑制显著改变了肿瘤微环境的基因表达谱，但对癌症转移没有显著影响。通过将Hh信号传导抑制剂BMS833923与RAS下游MEK信号传导抑制剂AZD 6244组合，我们在几种胰腺癌转移的小鼠模型中观察到转移结节的数量减少。这两种抑制剂还显著降低细胞增殖并减少CD45+细胞（特别是Ly6G + CD11b+细胞）。我们证明，去除Ly6G + CD11b+细胞足以减少癌细胞增殖和转移结节的数量。在体外，Ly6G + CD11b+细胞可以刺激癌细胞增殖，并且这种效应对MEK和Hh抑制敏感。我们的研究可能有助于设计新的治疗策略，以减轻胰腺癌转移。
Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal cancer types, with an estimated 44,330 death in 2018 in the US alone. While targeted therapies and immune checkpoint inhibitors have significantly improved treatment options for patients with lung cancer and renal cell carcinomas, little progress has been made in pancreatic cancer, with a dismal 5-year survival rate currently at ~8%. Upon diagnosis, the majority of pancreatic cancer cases (~80%) are already metastatic. Thus, identifying ways to reduce pancreatic cancer metastasis is an unmet medical need. Furthermore, pancreatic cancer is notorious resistant to chemotherapy. While Kirsten RAt Sarcoma virus oncogene (K-RAS) mutation is the major driver for pancreatic cancer, specific inhibition of RAS signaling has been very challenging, and combination therapy is thought to be promising. In this study, we report that combination of hedgehog (Hh) and Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase (MEK) signaling inhibitors reduces pancreatic cancer metastasis in mouse models. In mouse models of pancreatic cancer metastasis using human pancreatic cancer cells, we found that Hh target gene Gli1 is up-regulated during pancreatic cancer metastasis. Specific inhibition of smoothened signaling significantly altered the gene expression profile of the tumor microenvironment but had no significant effects on cancer metastasis. By combining Hh signaling inhibitor BMS833923 with RAS downstream MEK signaling inhibitor AZD6244, we observed reduced number of metastatic nodules in several mouse models for pancreatic cancer metastasis. These two inhibitors also decreased cell proliferation significantly and reduced CD45+ cells (particularly Ly6G+CD11b+ cells). We demonstrated that depleting Ly6G+ CD11b+ cells is sufficient to reduce cancer cell proliferation and the number of metastatic nodules. In vitro, Ly6G+ CD11b+ cells can stimulate cancer cell proliferation, and this effect is sensitive to MEK and Hh inhibition. Our studies may help design novel therapeutic strategies to mitigate pancreatic cancer metastasis.
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DOI：
10.1158/1078-0432.ccr-12-0032
发表时间：
2013-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chang Z;Li Z;Wang X;Kang Y;Yuan Y;Niu J;Wang H;Chatterjee D;Fleming JB;Li M;Abbruzzese JL;Chiao PJ
通讯作者：
Chiao PJ
影响因子：
50.3
作者：
Cooke VG;LeBleu VS;Keskin D;Khan Z;O'Connell JT;Teng Y;Duncan MB;Xie L;Maeda G;Vong S;Sugimoto H;Rocha RM;Damascena A;Brentani RR;Kalluri R
通讯作者：
Kalluri R
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
6.4
作者：
Kitadai, Yasuhiko;Sasaki, Takamitsu;Fidler, Isaiah J.
通讯作者：
Fidler, Isaiah J.
影响因子：
15.9
作者：
Leca, Julie;Martinez, Sebastien;Tomasini, Richard
通讯作者：
Tomasini, Richard