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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number698888
JournalFrontiers in Oncology
Volume11
DOIs
StatePublished - Jun 18 2021

Keywords

  • bilirubin
  • BRAF-mutant melanoma
  • ERK
  • MNK1
  • vemurafenib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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