Androgen deprivation induces phenotypic plasticity and promotes resistance to molecular targeted therapy in a PTEN-deficient mouse model of prostate cancer.
Androgen deprivation induces phenotypic plasticity and promotes resistance to molecular targeted therapy in a PTEN-deficient mouse model of prostate cancer.
复制标题
DOI：
10.1093/carcin/bgu143
复制
发表时间：
2014-09
期刊：
影响因子：
4.7
通讯作者：
Uemura H
中科院分区：
文献类型：
--
作者：
De Velasco MA;Tanaka M;Yamamoto Y;Hatanaka Y;Koike H;Nishio K;Yoshikawa K;Uemura H
向耐去势前列腺癌的转化推动了细胞的可塑性，从而促进了肿瘤内的异质性，并导致了治疗耐药性。去势抵抗前列腺癌是一种无法治愈的异质性疾病，其特征是一个复杂的多步骤过程，涉及由遗传和表观遗传改变引起的不同细胞和生化变化。这些变化导致关键生存通路的激活或过度表达，这些通路也是潜在的治疗靶点。尽管临床前的结果很有希望，但针对这些信号通路的分子靶向治疗到目前为止还很令人沮丧。在目前的研究中，我们使用了PTEN缺陷的前列腺癌小鼠模型来表明去势抵抗肿瘤的可塑性促进了治疗逃逸。与依赖雄激素受体和PI3K/AKT信号激活来生长和生存的去势幼稚肿瘤不同，去势抵抗肿瘤具有表型可塑性，导致肿瘤内异质性增加。这些肿瘤获得了高度异质性的表型，其特征是癌细胞依赖于不同的信号转导途径来生长和生存，如有丝分裂原激活的蛋白激酶和Janus激酶/信号转导和转录激活因子，并失去对PI3K信号的依赖。因此，这些特征使抗去势肿瘤对PI3K/AKT靶向治疗的疗效变得不敏感。总体而言，我们的发现提供了证据，表明雄激素剥夺推动了前列腺癌细胞的表型可塑性，并暗示它是耐去势前列腺癌治疗抵抗的关键因素。因此，在动态肿瘤模型中结合肿瘤内的异质性作为临床前疗效测定的一部分，可以改善对疗效的预测，并为开发更有效的治疗方法提供更好的理论基础。
The transformation to castration-resistant prostate cancer drives cell plasticity that promotes intra-tumor heterogeneity and contributes to therapeutic resistance. Castration-resistant prostate cancer is an incurable heterogeneous disease that is characterized by a complex multistep process involving different cellular and biochemical changes brought on by genetic and epigenetic alterations. These changes lead to the activation or overexpression of key survival pathways that also serve as potential therapeutic targets. Despite promising preclinical results, molecular targeted therapies aimed at such signaling pathways have so far been dismal. In the present study, we used a PTEN-deficient mouse model of prostate cancer to show that plasticity in castration-resistant tumors promotes therapeutic escape. Unlike castration-naïve tumors which depend on androgen receptor and PI3K/AKT signal activation for growth and survival, castration-resistant tumors undergo phenotypic plasticity leading to increased intratumoral heterogeneity. These tumors attain highly heterogeneous phenotypes that are characterized by cancer cells relying on alternate signal transduction pathways for growth and survival, such as mitogen-activated protein kinase and janus kinase/signal transducer and activator of transcription, and losing their dependence on PI3K signaling. These features thus enabled castration-resistant tumors to become insensitive to the therapeutic effects of PI3K/AKT targeted therapy. Overall, our findings provide evidence that androgen deprivation drives phenotypic plasticity in prostate cancer cells and implicate it as a crucial contributor to therapeutic resistance in castration-resistant prostate cancer. Therefore, incorporating intratumoral heterogeneity in a dynamic tumor model as a part of preclinical efficacy determination could improve prediction for response and provide better rationale for the development of more effective therapies.
登录
查看更多内容
影响因子：
3.9
作者：
Ha S;Ruoff R;Kahoud N;Franke TF;Logan SK
通讯作者：
Logan SK
受体酪氨酸激酶的可发展信号网络：鲁棒性与恶性肿瘤和癌症治疗的相关性。
影响因子：
9.9
作者：
Amit, Ido;Wides, Ron;Yarden, Yosef
通讯作者：
Yarden, Yosef
影响因子：
11.2
作者：
Floc'h N;Kinkade CW;Kobayashi T;Aytes A;Lefebvre C;Mitrofanova A;Cardiff RD;Califano A;Shen MM;Abate-Shen C
通讯作者：
Abate-Shen C
影响因子：
50.3
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
82.9
作者：
Majumder, PK;Febbo, PG;Sellers, WR
通讯作者：
Sellers, WR