Sorafenib and Quinacrine Target Anti-Apoptotic Protein MCL1: A Poor Prognostic Marker in Anaplastic Thyroid Cancer (ATC).
OBJECTIVE
Anaplastic thyroid cancer (ATC) comprises approximately 2% of all thyroid cancers, and its median survival rate remains poor. It is responsible for more than one third of thyroid cancer-related deaths. ATC is frequently resistant to conventional therapy, and NFκB signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the antimalaria drug quinacrine known to target NFκB signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFκB-p65/RELA and its target MCL1 was demonstrated in ATC by meta-data gene set enrichment analysis and IHC. We assessed the responses of a panel of human ATC cell lines to quinacrine and sorafenib in vitro and in vivo RESULTS: We detected increased expression of NFκB-p65/RELA and MCL1 in the nucleus of a subset of ATC compared with non-neoplastic thyroid. ATC cells were found to respond with additive/synergistic tumor cell killing to the combination of sorafenib plus quinacrine in vitro, and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC cells as compared with mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and quinacrine is well tolerated in mice. At the molecular level, quinacrine and sorafenib inhibited expression of prosurvival MCL1, pSTAT3, and dampened NFκB signaling.


CONCLUSIONS
The combination of quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus quinacrine can be conducted in ATC patients. Clin Cancer Res; 22(24); 6192-203. ©2016 AACR.
Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, Pennsylvania.|Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Junaid
J
Abdulghani
Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, Pennsylvania.|Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Prashanth
P
Gokare
Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, Pennsylvania.
Jean-Nicolas
JN
Gallant
Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, Pennsylvania.|Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
David
D
Dicker
Department of Comparative Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania.
Tiffany
T
Whitcomb
Department of Comparative Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania.
Timothy
T
Cooper
Department of Public Health Sciences, Penn State Hershey Medical Center, Hershey, Pennsylvania.
Jiangang
J
Liao
Department of Surgery; Division of Otolaryngology-Head and Neck Surgery, Penn State Hershey Medical Center, Hershey, Pennsylvania.
Jonathan
J
Derr
Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston Medical School, Houston, Texas.
Jing
J
Liu
Department of Surgery; Division of Otolaryngology-Head and Neck Surgery, Penn State Hershey Medical Center, Hershey, Pennsylvania.
David
D
Goldenberg
Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, Pennsylvania. wafik.eldeiry@fccc.edu niklas.finnberg@fccc.edu.|Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Niklas K
NK
Finnberg
Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, Pennsylvania. wafik.eldeiry@fccc.edu niklas.finnberg@fccc.edu.|Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Wafik S
WS
El-Deiry
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology*; D000077157:Sorafenib; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000378:metabolism*; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D051996:Transcription Factor RelA; D009536:Niacinamide; D004317:Doxorubicin; D000077157:Sorafenib; D011796:Quinacrine