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.
Highlights
Malignant melanoma is one of the most aggressive cancer that initially develops from melanocytes [1], accounting for approximately 90,000 newly diagnosed cases and 10,000 deaths each year [2]
The results showed that the time of total bilirubin (TBIL), direct bilirubin (DBIL), or indirect bilirubin (IBIL) below the threshold level was positively correlated with the clinical outcome of these patients (Figures 1A–C)
These findings demonstrate that blood bilirubin predicts the poor outcome for melanoma patients, and may act as a negative factor in the treatment of BRAF mutant melanoma with vemurafenib
Summary
Malignant melanoma is one of the most aggressive cancer that initially develops from melanocytes [1], accounting for approximately 90,000 newly diagnosed cases and 10,000 deaths each year [2]. The highly activated MAPK signaling pathway results from alterations of the BRAF and NRAS genes is the key driver for the development and progression of the majority of cutaneous melanoma [5, 6]. There are several identified molecular mechanisms underlying the acquired resistance to vemurafenib, including but not limited to NRAS mutation, emergence of BRAF splicing, and BRAF amplification [11,12,13]. These mechanisms cannot explain resistance to BRAF inhibitors in approximately 40% of cases [14, 15]. It is necessary to further eliminate the vemurafenib resistance beyond the genetic modification to fight cutaneous melanoma
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