2. Academic Validation
  3. Disulfiram/Cu Kills and Sensitizes BRAF-Mutant Thyroid Cancer Cells to BRAF Kinase Inhibitor by ROS-Dependently Relieving Feedback Activation of MAPK/ERK and PI3K/AKT Pathways

Disulfiram/Cu Kills and Sensitizes BRAF-Mutant Thyroid Cancer Cells to BRAF Kinase Inhibitor by ROS-Dependently Relieving Feedback Activation of MAPK/ERK and PI3K/AKT Pathways

  • Int J Mol Sci. 2023 Feb 8;24(4):3418. doi: 10.3390/ijms24043418.
Jingyi Xie 1 2,  Juan Liu 1 2,  Man Zhao 1 2,  Xinru Li 1 2,  Yubo Wang 1 2,  Yuelei Zhao 1 2,  Hongxin Cao 1 2,  Meiju Ji 3,  Mingwei Chen 4,  Peng Hou 1 2
Affiliations

Affiliations

  • 1 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 2 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 3 Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 4 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
PMID: 36834830 DOI: 10.3390/ijms24043418
Abstract

BRafV600E, the most common genetic alteration, has become a major therapeutic target in thyroid Cancer. Vemurafenib (PLX4032), a specific inhibitor of BRafV600E kinase, exhibits antitumor activity in patients with BRafV600E-mutated thyroid Cancer. However, the clinical benefit of PLX4032 is often limited by short-term response and acquired resistance via heterogeneous feedback mechanisms. Disulfiram (DSF), an alcohol-aversion drug, shows potent antitumor efficacy in a copper (Cu)-dependent way. However, its antitumor activity in thyroid Cancer and its effect on cellular response to BRaf kinase inhibitors remain unclear. Antitumor effects of DSF/Cu on BRafV600E-mutated thyroid Cancer cells and its effect on the response of these cells to BRaf kinase inhibitor PLX4032 were systematically assessed by a series of in vitro and in vivo functional experiments. The molecular mechanism underlying the sensitizing effect of DSF/Cu on PLX4032 was explored by Western blot and flow cytometry assays. DSF/Cu exhibited stronger inhibitory effects on the proliferation and colony formation of BRafV600E-mutated thyroid Cancer cells than DSF treatment alone. Further studies revealed that DSF/Cu killed thyroid Cancer cells by ROS-dependent suppression of MAPK/ERK and PI3K/Akt signaling pathways. Our data also showed that DSF/Cu strikingly increased the response of BRafV600E-mutated thyroid Cancer cells to PLX4032. Mechanistically, DSF/Cu sensitizes BRaf-mutant thyroid Cancer cells to PLX4032 by inhibiting HER3 and Akt in an ROS-dependent way and subsequently relieving feedback activation of MAPK/ERK and PI3K/Akt pathways. This study not only implies potential clinical use of DSF/Cu in Cancer therapy but also provides a new therapeutic strategy for BRafV600E-mutated thyroid cancers.

Keywords

BRAF kinase inhibitor; HER3; disulfiram/Cu; sensitizing effect; thyroid cancer.

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