title: Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression.
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.
authors.affiliation: 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.
authors.forename: Devora
authors.initials: D
authors.lastname: Champa
authors.affiliation: 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.
authors.forename: Marika A
authors.initials: MA
authors.lastname: Russo
authors.affiliation: 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.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Liao
authors.affiliation: 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.
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.affiliation: 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.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Ghossein
authors.affiliation: 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.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Cristofano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048730:MAP Kinase Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D007211:Indoles; C579094:Mcl1 protein, mouse; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D012333:RNA, Messenger; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; C520962:obatoclax
keywords: cell death; mouse model; thyroid cancer