Bilirubin Restrains the Anticancer Effect of Vemurafenib on BRAF-Mutant Melanoma Cells Through ERK-MNK1 Signaling

Yufan Tan; Xiaoyu Zhong; Xizhi Wen; Leyi Yao; Zhenlong Shao; Wenshuang Sun; Jiawen Wu; Guanmei Wen; Daolin Tang; Xiaoshi Zhang; Yuning Liao; Jinbao Liu

doi:10.3389/fonc.2021.698888

Bilirubin Restrains the Anticancer Effect of Vemurafenib on BRAF-Mutant Melanoma Cells Through ERK-MNK1 Signaling

Front Oncol. 2021 Jun 18:11:698888. doi: 10.3389/fonc.2021.698888. eCollection 2021.

Authors

Yufan Tan¹, Xiaoyu Zhong^{1

2}, Xizhi Wen³, Leyi Yao¹, Zhenlong Shao¹, Wenshuang Sun¹, Jiawen Wu¹, Guanmei Wen¹, Daolin Tang⁴, Xiaoshi Zhang³, Yuning Liao^{1

2}, Jinbao Liu^{1

2}

Affiliations

¹ Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
² Institute of Digestive Disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.
³ Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
⁴ Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, United States.

Abstract

Melanoma, the most threatening cancer in the skin, has been considered to be driven by the carcinogenic RAF-MEK1/2-ERK1/2 signaling pathway. This signaling pathway is usually mainly dysregulated by mutations in BRAF or RAS in skin melanomas. Although inhibitors targeting mutant BRAF, such as vemurafenib, have improved the clinical outcome of melanoma patients with BRAF mutations, the efficiency of vemurafenib is limited in many patients. Here, we show that blood bilirubin in patients with BRAF-mutant melanoma treated with vemurafenib is negatively correlated with clinical outcomes. In vitro and animal experiments show that bilirubin can abrogate vemurafenib-induced growth suppression of BRAF-mutant melanoma cells. Moreover, bilirubin can remarkably rescue vemurafenib-induced apoptosis. Mechanically, the activation of ERK-MNK1 axis is required for bilirubin-induced reversal effects post vemurafenib treatment. Our findings not only demonstrate that bilirubin is an unfavorable for patients with BRAF-mutant melanoma who received vemurafenib treatment, but also uncover the underlying mechanism by which bilirubin restrains the anticancer effect of vemurafenib on BRAF-mutant melanoma cells.

Keywords: BRAF-mutant melanoma; ERK; MNK1; bilirubin; vemurafenib.