Sorafenib and Quinacrine Target Anti-Apoptotic Protein MCL1: A Poor Prognostic Marker in Anaplastic Thyroid Cancer (ATC)

Purpose and Experimental Design: 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.

[1]  Stephanie L. Lee,et al.  Anaplastic Thyroid Cancer: Outcome and the Mutation/Expression Profiles of Potential Targets , 2015, Pathology & Oncology Research.

[2]  R. Paschke,et al.  Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial , 2014, The Lancet.

[3]  S. Desagher,et al.  Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein , 2014, Cells.

[4]  P. Toti,et al.  The role of survivin in thyroid tumors: differences of expression in well-differentiated, non-well-differentiated, and anaplastic thyroid cancers. , 2014, Thyroid : official journal of the American Thyroid Association.

[5]  Lei Feng,et al.  Sorafenib in metastatic thyroid cancer: a systematic review. , 2014, The oncologist.

[6]  Xinmin Zhou,et al.  Regulation of Mcl-1 by constitutive activation of NF-kappaB contributes to cell viability in human esophageal squamous cell carcinoma cells , 2014, BMC Cancer.

[7]  M. Schabel,et al.  Quinacrine synergistically enhances the antivascular and antitumor efficacy of cediranib in intracranial mouse glioma. , 2013, Neuro-oncology.

[8]  W. El-Deiry,et al.  Sorafenib Sensitizes Solid Tumors to Apo2L/TRAIL and Apo2L/TRAIL Receptor Agonist Antibodies by the Jak2-Stat3-Mcl1 Axis , 2013, PloS one.

[9]  J. Wright,et al.  Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid. , 2013, Thyroid : official journal of the American Thyroid Association.

[10]  M. Dewaele,et al.  mRNA Expression in Papillary and Anaplastic Thyroid Carcinoma: Molecular Anatomy of a Killing Switch , 2012, PloS one.

[11]  J. Fagin,et al.  STAT3 negatively regulates thyroid tumorigenesis , 2012, Proceedings of the National Academy of Sciences.

[12]  Keiji Suzuki,et al.  Imatinib enhances docetaxel-induced apoptosis through inhibition of nuclear factor-κB activation in anaplastic thyroid carcinoma cells. , 2012, Thyroid : official journal of the American Thyroid Association.

[13]  L. Wirth,et al.  Survival of a patient with anaplastic thyroid cancer following intensity-modulated radiotherapy and sunitinib--a case report. , 2012, Anticancer research.

[14]  W. El-Deiry,et al.  Quinacrine synergizes with 5-fluorouracil and other therapies in colorectal cancer , 2011, Cancer biology & therapy.

[15]  Sharyn I. Katz,et al.  Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents , 2011, Cancer biology & therapy.

[16]  S. Remick,et al.  Anaplastic Thyroid Cancer: A Review of Epidemiology, Pathogenesis, and Treatment , 2011, Journal of oncology.

[17]  S. Feller,et al.  Beyond DNA binding - a review of the potential mechanisms mediating quinacrine's therapeutic activities in parasitic infections, inflammation, and cancers , 2011, Cell Communication and Signaling.

[18]  Ge Zhou,et al.  Targeted Therapy of VEGFR2 and EGFR Significantly Inhibits Growth of Anaplastic Thyroid Cancer in an Orthotopic Murine Model , 2011, Clinical Cancer Research.

[19]  Kendall W. Cradic,et al.  Detailed molecular fingerprinting of four new anaplastic thyroid carcinoma cell lines and their use for verification of RhoB as a molecular therapeutic target. , 2010, The Journal of clinical endocrinology and metabolism.

[20]  Robert E. Brown,et al.  Immunohistochemical detection of epithelialmesenchymal transition associated with stemness phenotype in anaplastic thyroid carcinoma. , 2010, International journal of clinical and experimental pathology.

[21]  M. Shah,et al.  New therapeutic advances in the management of progressive thyroid cancer. , 2009, Endocrine-related cancer.

[22]  M. Shu,et al.  A Small-Molecule Triptolide Suppresses Angiogenesis and Invasion of Human Anaplastic Thyroid Carcinoma Cells via Down-Regulation of the Nuclear Factor-κB Pathway , 2009, Molecular Pharmacology.

[23]  Thomas S. Lin,et al.  Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab. , 2009, Blood.

[24]  D. Elder,et al.  CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations , 2009, Oncogene.

[25]  S. Paggi,et al.  Sorafenib in advanced hepatocellular carcinoma. , 2008, The New England journal of medicine.

[26]  J. Copland,et al.  Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. , 2008, Endocrine-related cancer.

[27]  H. Namba,et al.  Dehydroxymethylepoxyquinomicin, a novel nuclear Factor-kappaB inhibitor, enhances antitumor activity of taxanes in anaplastic thyroid cancer cells. , 2008, Endocrinology.

[28]  Christopher Korch,et al.  Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. , 2008, The Journal of clinical endocrinology and metabolism.

[29]  Andrea B Troxel,et al.  Phase II trial of sorafenib in advanced thyroid cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  J. Llovet,et al.  Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling , 2008, Molecular Cancer Therapeutics.

[31]  B. Leiby,et al.  Stat3 promotes metastatic progression of prostate cancer. , 2008, The American journal of pathology.

[32]  M. Bittner,et al.  A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. , 2007, Cancer research.

[33]  Seungwon Kim,et al.  The Tyrosine Kinase Inhibitor, AZD2171, Inhibits Vascular Endothelial Growth Factor Receptor Signaling and Growth of Anaplastic Thyroid Cancer in an Orthotopic Nude Mouse Model , 2007, Clinical Cancer Research.

[34]  K. Flaherty,et al.  Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. , 2007, Cancer cell.

[35]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[36]  Bhuvanesh Singh,et al.  Patterns of expression of cell cycle/apoptosis genes along the spectrum of thyroid carcinoma progression. , 2006, Surgery.

[37]  D. McMillin,et al.  Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro. , 2006, The Journal of clinical endocrinology and metabolism.

[38]  Ting-Chao Chou,et al.  Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies , 2006, Pharmacological Reviews.

[39]  David E. Misek,et al.  Delineation, Functional Validation, and Bioinformatic Evaluation of Gene Expression in Thyroid Follicular Carcinomas with the PAX8-PPARG Translocation , 2006, Clinical Cancer Research.

[40]  A. Shaha,et al.  Poorly differentiated and anaplastic thyroid cancer. , 2006, Cancer control : journal of the Moffitt Cancer Center.

[41]  G. Stark,et al.  Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53 suppression in tumors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[42]  David E. Misek,et al.  Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis , 2005, Oncogene.

[43]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  M. Mandal,et al.  An Orthotopic Model of Anaplastic Thyroid Carcinoma in Athymic Nude Mice , 2005, Clinical Cancer Research.

[45]  A. Leonardi,et al.  Oncogenic and Anti-apoptotic Activity of NF-κB in Human Thyroid Carcinomas* , 2004, Journal of Biological Chemistry.

[46]  T. Kurihara,et al.  Immunohistochemical and sequencing analyses of the Wnt signaling components in Japanese anaplastic thyroid cancers. , 2004, Thyroid : official journal of the American Thyroid Association.

[47]  B. Rayet,et al.  Aberrant rel/nfkb genes and activity in human cancer , 1999, Oncogene.

[48]  P. Brousset,et al.  Expression of the cell death-inducing gene bax in carcinomas developed from the follicular cells of the thyroid gland. , 1996, The Journal of clinical endocrinology and metabolism.

[49]  T. Seyama,et al.  Establishment of 2 human thyroid-carcinoma cell-lines (8305c, 8505c) bearing p53 gene-mutations. , 1994, International journal of oncology.

[50]  A. Leonardi,et al.  NGAL controls the metastatic potential of anaplastic thyroid carcinoma cells. , 2013, The Journal of clinical endocrinology and metabolism.

[51]  Jing Liu,et al.  Morphoproteomic confirmation of an activated nuclear factor-кBp65 pathway in follicular thyroid carcinoma. , 2012, International journal of clinical and experimental pathology.

[52]  R. Gascoyne,et al.  Short Communication Immunohistochemical Analysis of Mci-1 Protein in Human Tissues Differential Regulation of Mcl- 1 and Bcl-2 Protein Production Suggests a Unique Role for Mcl- 1 in Control of Programmed Cell Death In Vivo , 2007 .

[53]  A. Leonardi,et al.  Oncogenic and anti-apoptotic activity of NF-kappa B in human thyroid carcinomas. , 2004, The Journal of biological chemistry.