Sorafenib and quinacrine target anti-apoptotic protein MCL1: A poor prognostic marker in Anaplastic Thyroid Cancer (ATC)

Junaid Abdulghani, Prashanth Gokare, Jean Nicolas Gallant, David Dicker, Tiffany Whitcomb, Timothy Cooper, Jiangang (Jason) Liao, Jonathan Derr, Jing Liu, David Goldenberg, Niklas K. Finnberg, Wafik S. El-Deiry

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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 nonneoplastic 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.

Original languageEnglish (US)
Pages (from-to)6192-6203
Number of pages12
JournalClinical Cancer Research
Volume22
Issue number24
DOIs
StatePublished - Dec 15 2016

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Quinacrine
Apoptosis Regulatory Proteins
Thyroid Neoplasms
Anaplastic Thyroid Carcinoma
sorafenib
Drug Combinations
Doxorubicin
Thyroid Gland
Research Design
Phosphotransferases

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Abdulghani, Junaid ; Gokare, Prashanth ; Gallant, Jean Nicolas ; Dicker, David ; Whitcomb, Tiffany ; Cooper, Timothy ; Liao, Jiangang (Jason) ; Derr, Jonathan ; Liu, Jing ; Goldenberg, David ; Finnberg, Niklas K. ; El-Deiry, Wafik S. / Sorafenib and quinacrine target anti-apoptotic protein MCL1 : A poor prognostic marker in Anaplastic Thyroid Cancer (ATC). In: Clinical Cancer Research. 2016 ; Vol. 22, No. 24. pp. 6192-6203.
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abstract = "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 nonneoplastic 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.",
author = "Junaid Abdulghani and Prashanth Gokare and Gallant, {Jean Nicolas} and David Dicker and Tiffany Whitcomb and Timothy Cooper and Liao, {Jiangang (Jason)} and Jonathan Derr and Jing Liu and David Goldenberg and Finnberg, {Niklas K.} and El-Deiry, {Wafik S.}",
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Sorafenib and quinacrine target anti-apoptotic protein MCL1 : A poor prognostic marker in Anaplastic Thyroid Cancer (ATC). / Abdulghani, Junaid; Gokare, Prashanth; Gallant, Jean Nicolas; Dicker, David; Whitcomb, Tiffany; Cooper, Timothy; Liao, Jiangang (Jason); Derr, Jonathan; Liu, Jing; Goldenberg, David; Finnberg, Niklas K.; El-Deiry, Wafik S.

In: Clinical Cancer Research, Vol. 22, No. 24, 15.12.2016, p. 6192-6203.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sorafenib and quinacrine target anti-apoptotic protein MCL1

T2 - A poor prognostic marker in Anaplastic Thyroid Cancer (ATC)

AU - Abdulghani, Junaid

AU - Gokare, Prashanth

AU - Gallant, Jean Nicolas

AU - Dicker, David

AU - Whitcomb, Tiffany

AU - Cooper, Timothy

AU - Liao, Jiangang (Jason)

AU - Derr, Jonathan

AU - Liu, Jing

AU - Goldenberg, David

AU - Finnberg, Niklas K.

AU - El-Deiry, Wafik S.

PY - 2016/12/15

Y1 - 2016/12/15

N2 - 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 nonneoplastic 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.

AB - 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 nonneoplastic 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.

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