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Endocr Relat Cancer. 2014 Oct;21(5):755-67. doi: 10.1530/ERC-14-0268. Epub 2014 Jul 10.

Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression.

Author information

1
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.
2
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.
3
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 antonio.dicristofano@einstein.yu.edu.

Abstract

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.

KEYWORDS:

cell death; mouse model; thyroid cancer

PMID:
25012986
PMCID:
PMC4152557
DOI:
10.1530/ERC-14-0268
[Indexed for MEDLINE]
Free PMC Article
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