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Encorafenib (LGX818), a Potent BRAF Inhibitor, Induces Senescence Accompanied by Autophagy in BRAFV600E Melanoma Cells

Encorafenib (LGX818), a Potent BRAF Inhibitor, Induces Senescence Accompanied by Autophagy in BRAFV600E Melanoma Cells

Zhen Li, Ke Jiang, Xiaofang Zhu, Guibin Lin, Fei Song, Yongfu Zhao, Yongjun Piao, Jiwei Liu, Wei Cheng, Xiaolin Bi, Peng Gong, Zhiqi Song, Songshu Meng

Cancer Lett. 2016 Jan 28;370(2):332-44.

PMID: 26586345

Abstract:

Encorafenib (LGX818) is a new-generation BRAF inhibitor that is under evaluation in clinical trials. However, the underlying mechanism remains to be elucidated. Here we show that LGX818 potently decreased ERK phosphorylation and inhibited proliferation in BRAFV600E melanoma cell lines. Moreover, LGX818 downregulated CyclinD1 in a glycogen synthase kinase 3β-independent manner and induced cell cycle arrest in the G1 phase, Surprisingly, LGX818 triggered cellular senescence in BRAFV600E melanoma cells, as evidenced by increased β-galactosidase staining, while no appreciable induction of apoptosis was detected, as determined by Annexin V and propidium iodide staining and immunoblot analysis of caspase-3 processing and poly (ADP-ribose) polymerase cleavage. Increased p27KIP1 expression and retinoblastoma protein activation were detected during LGX818-induced senescence. Additionally, inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 1B by AZ191 reversed LGX818-induced CyclinD1 turnover and senescence. Interestingly, autophagy is triggered through inhibition of the mTOR/70S6K pathway during LGX818-induced senescence. Moreover, autophagy inhibition by pharmacological and genetic regulation attenuates LGX818-induced senescence. Notably, combining LGX818 with autophagy modulators has anti-proliferative effect in LGX818-resistant BRAF mutant melanoma cells. Altogether, we uncovered a mechanism by which LGX818 exerts its anti-tumor activity in BRAFV600E melanoma cells.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1594092371	AZ191		1594092-37-1	Price

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