Champa Devora, Russo Marika A, Liao Xiao-Hui, Refetoff Samuel, Ghossein Ronald A, Di Cristofano Antonio
Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA.
Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA.
Endocr Relat Cancer. 2014 Oct;21(5):755-67. doi: 10.1530/ERC-14-0268. Epub 2014 Jul 10.
Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 (Trp53) in thyroid follicular cells, we have generated a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma-derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members, Bcl2a1 (Bcl2a1a) and Mcl1, and can be effectively targeted by Obatoclax, a small-molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model have uncovered a promising druggable feature of aggressive thyroid cancers.
甲状腺低分化肿瘤（PDTC）通常预后较差，因为它们对现有的治疗方法具有抗性。这些肿瘤相对罕见，这是我们理解导致肿瘤侵袭性和耐药性的分子机制以及开发新疗法的主要障碍。通过在甲状腺滤泡细胞中同时激活Kras并删除p53（Trp53），我们建立了一种新型小鼠模型，该模型会发展为乳头状甲状腺癌，并始终进展为PDTC。在某些情况下，肿瘤会进一步发展为间变性癌。这些低分化肿瘤在形态和功能上与其人类对应物相似，并且依赖MEK/ERK信号进行增殖。使用原发性癌以及癌衍生的细胞系，我们还证明这些肿瘤由于Bcl2家族成员Bcl2a1（Bcl2a1a）和Mcl1的高表达而对凋亡具有内在抗性，并且可以被Obatoclax有效靶向，Obatoclax是一种Bcl2家族的小分子泛抑制剂。此外，我们表明Bcl2家族抑制与MEK抑制以及阿霉素在诱导细胞死亡方面具有协同作用。因此，我们在一个新型的、相关的小鼠模型中的研究揭示了侵袭性甲状腺癌一个有前景的可药物靶向特征。
