Oncotarget

Research Papers:

HER inhibitor promotes BRAF/MEK inhibitor-induced redifferentiation in papillary thyroid cancer harboring BRAFV600E

Lingxiao Cheng, Yuchen Jin, Min Liu, Maomei Ruan and Libo Chen _

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Oncotarget. 2017; 8:19843-19854. https://doi.org/10.18632/oncotarget.15773

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Abstract

Lingxiao Cheng1,*, Yuchen Jin1,*, Min Liu1, Maomei Ruan2, Libo Chen1

1Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China

2Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China

*Co-first authors

Correspondence to:

Libo Chen, email: [email protected]

Keywords: papillary thyroid cancer, redifferentiation, iodine, glucose, dabrafenib

Received: October 20, 2016     Accepted: January 24, 2017     Published: February 28, 2017

ABSTRACT

Redifferentiation therapy with BRAF/MEK inhibitors to facilitate treatment with radioiodine represents a good choice for radioiodine-refractory differentiated thyroid carcinoma, but recent initial clinical outcomes were modest. MAPK rebound caused by BRAF/MEK inhibitors-induced activation of HER2/HER3 is a resistance mechanism, and combination with HER inhibitor to prevent MAPK rebound may sensitize BRAFV600E-mutant thyroid cancer cells to redifferentiation therapy. To evaluate if inhibiting both BRAF/MEK and HER can produce stronger redifferetiation effect, we tested the effects of BRAF/MEK inhibitor dabrafenib/selumetinib alone or in combination with HER inhibitor lapatinib on the expression and function of iodine- and glucose-handling genes in BRAFV600E-positive BCPAP and K1 cells, using BHP 2-7 cells harboring RET/PTC1 rearrangement as control. Herein, we showed that lapatinib prevented MAPK rebound and sensitized BRAFV600E-positive papillary thyroid cancer cells to BRAF/MEK inhibitors. Dabrafenib/selumetinib alone increased iodine-uptake and toxicity and suppressed glucose-metablism in BRAFV600E-positive papillary thyroid cancer cells. When lapatinib was added, more significant effects on iodine- and glucose-handling gene expression, cell membrane location of sodium/iodine symporter as well as radioiodine uptake and toxicity were observed. Thus, combined therapy using HER inhibitor and BRAF/MEK inhibitor presented more significant redifferentiation effect on papillary thyroid cancer cells harboring BRAFV600E than BRAF/MEK inhibitor alone. In vivo and clinical studies assessing such combined targeted redifferentiation strategy were warranted.


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