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SoLAT (Sorafenib Lenvatinib alternating treatment): a new treatment protocol with altnernating Sorafenib and Lenvatinib for refractory thyroid cancer

Authors
 Soo Young Kim  ;  Seok-Mo Kim  ;  Ho-Jin Chang  ;  Bup-Woo Kim  ;  Yong Sang Lee  ;  Cheong Soo Park  ;  Ki Cheong Park  ;  Hang-Seok Chang 
Citation
 BMC Cancer, Vol.18(1) : 956, 2018 
Journal Title
 BMC Cancer 
Issue Date
2018
Keywords
EMT ; FGF signaling ; Lenvatinib ; Papillary thyroid cancer ; Sorafenib ; TKI
Abstract
BACKGROUND: In the last decade, several tyrosine kinase inhibitors (TKIs), which disrupt pathways involved in the proliferation and tumorigenesis of thyroid cancer, have been extensively studied. Two different TKIs, lenvatinib and sorafenib, were recently approved by both the US FDA and European Medicine Agency. Until date, the duration of the TKI response is not sufficient and resistance eventually occurs. The goal of this study was to investigate a new treatment protocol, SoLAT, using sorafenib and lenvatinib alternatively on refractory thyroid cancer. METHODS: Patient-derived aggressive papillary thyroid cancer (PTC) cell lines from patients with biochemical and histologically proven aggressive RAI-refractory papillary thyroid cancer were exposed to sorafenib and lenvatinib alternatively. Human thyroid cancer cell xenografts were obtained by injecting patient-derived aggressive PTC cell lines into the flank of female BALB/c nude mice. Tumor-bearing mice were treated with sorafenib and lenvatinib alternatively. Cell viability assay, immunofluorescence analysis, confocal imaging, immunoblot analysis, flow cytometry analysis of cell cycle and a tube formation assay were performed. RESULTS: SoLAT was more effective for advanced PTC cell lines than individual treatment. Immunoblot analysis showed that SoLAT markedly increased levels of cell cycle inhibitors (p53 and p21), and pro-apoptotic factors (Apaf-1 and cleaved caspase 3) and decreased levels of positive cell cycle regulators (cyclin D1, CDK4, CDK6) and anti-apoptotic factors (p-NFκB, Bcl-2). Increased sub-G0/G1 population was observed in the SoLAT group, leading to apoptosis, cell cycle arrest, and strong inhibition of advanced PTC cell viability. SoLAT reduced the level of EMT markers such as vimentin, E-cadherin, Snail and Zeb1 by FGFR inhibition. In the xenograft model, individual treatment with sorafenib or lenvatinib did not markedly suppress patient-derived aggressive PTC cell xenograft tumors, whereas SoLAT significantly suppressed the proliferation of these tumors. CONCLUSIONS: SoLAT was more effective than individual treatment with sorafenib or lenvatinib in inhibiting PTC progression by inducing cell cycle arrest. Studies using both in vitro cell culture and an in vivo xenograft model provided evidence of tumor shrinkage with SoLAT. We suggest that these effects may be due to reduced EMT-mediated drug resistance in the aggressive PTC model
Files in This Item:
T201803405.pdf Download
DOI
10.1186/s12885-018-4854-z
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Bup Woo(김법우) ORCID logo https://orcid.org/0000-0002-1342-9055
Kim, Seok Mo(김석모) ORCID logo https://orcid.org/0000-0001-8070-0573
Kim, Soo Young(김수영) ORCID logo https://orcid.org/0000-0002-8919-3456
Park, Ki Cheong(박기청) ORCID logo https://orcid.org/0000-0002-3435-3985
Park, Cheong Soo(박정수)
Lee, Yong Sang(이용상) ORCID logo https://orcid.org/0000-0002-8234-8718
Chang, Hang Seok(장항석) ORCID logo https://orcid.org/0000-0002-5162-103X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/163741
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