VCAM-1 Upregulation Contributes to Insensitivity of Vemurafenib in BRAF-Mutant Thyroid Cancer

Shitu Chen; Xingyun Su; Xiaoxia Jiang; Tuo Zhang; Irene Min; Yongfeng Ding; Xumeng Wang; Zhuochao Mao; Jiang Cao; Xiaodong Teng; Thomas J. Fahey, III; Weibin Wang; Lisong Teng

Translational Oncology (Feb 2020)

VCAM-1 Upregulation Contributes to Insensitivity of Vemurafenib in BRAF-Mutant Thyroid Cancer

Shitu Chen,
Xingyun Su,
Xiaoxia Jiang,
Tuo Zhang,
Irene Min,
Yongfeng Ding,
Xumeng Wang,
Zhuochao Mao,
Jiang Cao,
Xiaodong Teng,
Thomas J. Fahey, III,
Weibin Wang,
Lisong Teng

Affiliations

Shitu Chen: Cancer Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Xingyun Su: Cancer Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Xiaoxia Jiang: Cancer Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Tuo Zhang: Genomic Core, Weill Cornell Medical College, New York, NY, USA
Irene Min: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, USA
Yongfeng Ding: Cancer Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Xumeng Wang: Cancer Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Zhuochao Mao: Cancer Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Jiang Cao: Clinical Research Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Xiaodong Teng: Department of Pathology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Thomas J. Fahey, III: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, USA; Thomas J. Fahey, Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, USA.
Weibin Wang: Cancer Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Weibin Wang, Cancer Center, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang, China.
Lisong Teng: Cancer Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Address all correspondence to: Lisong Teng, Cancer Center, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.

Journal volume & issue: Vol. 13, no. 2
pp. 441 – 451

Abstract

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Vemurafenib, an inhibitor of mutant BRAF activity, is a promising anticancer agent for patients with BRAF-mutant metastatic melanoma. However, it is less effective in BRAF-mutant thyroid cancer, and the reason for this discrepancy is not yet fully elucidated. By RNA sequencing analysis, we identified vascular cell adhesion molecular-1 (VCAM-1) to be highly upregulated in both time- and dose-dependent manners during BRAF inhibition (BRAFi) in a BRAF-mutant papillary thyroid cancer cell line (BCPAP). Cell cytotoxicity and apoptosis assays showed that knockdown of the induced VCAM-1 in BCPAP cells augmented the antitumor effects of vemurafenib, with decreased IC50 values of 1.4 to 0.8 μM. Meanwhile, overexpression of VCAM-1 in a BRAF-mutant anaplastic thyroid cancer cell line (FRO) reduced the sensitivity to vemurafenib, with increased IC50 values of 1.9 to 5.8 μM. Further investigation showed that PI3K-Akt-mTOR pathway was activated during BRAFi. Co-treatment with Akt signaling inhibitor MK2206 decreased the induced expression of VCAM-1 during BRAFi. This combination further improved the efficacy of vemurafenib. Moreover, VCAM-1 promoted migration and invasion in thyroid cancer cells in vitro, which was also indicated in thyroid cancer patients. The present study is the first to demonstrate that VCAM-1 is upregulated in thyroid cancer cells treated with vemurafenib and contributes to vemurafenib resistance in BRAF-mutant thyroid cancer cells. Targeting the PI3K-Akt-mTOR pathway–mediated VCAM-1 response may be an alternative strategy to sensitize BRAF-mutant thyroid cancers to vemurafenib.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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