title: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells.
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.
authors.affiliation: Department of Dermatology of First Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, No. 222 Zhongshan Road, Dalian 116021, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, Dalian 116044, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Dermatology, Clinical Medical School of Yangzhou University, 98 Nantong West Rd, Yangzhou 225001, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, Dalian 116044, China.
authors.forename: Guibin
authors.initials: G
authors.lastname: Lin
authors.affiliation: Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.affiliation: Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Dermatology of First Affiliated Hospital, Dalian Medical University, No. 222 Zhongshan Road, Dalian 116021, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Piao
authors.affiliation: First Affiliated Hospital, Dalian Medical University, No. 222 Zhongshan Road, Dalian 116021, China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, Dalian 116044, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, Dalian 116044, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Bi
authors.affiliation: First Affiliated Hospital, Dalian Medical University, No. 222 Zhongshan Road, Dalian 116021, China. Electronic address: gongpengdalian@163.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Gong
authors.affiliation: Department of Dermatology of First Affiliated Hospital, Dalian Medical University, No. 222 Zhongshan Road, Dalian 116021, China. Electronic address: szqdalian@163.com.
authors.forename: Zhiqi
authors.initials: Z
authors.lastname: Song
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, Dalian 116044, China. Electronic address: ssmeng@dmu.edu.cn.
authors.forename: Songshu
authors.initials: S
authors.lastname: Meng
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D002219:Carbamates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000097603:Dyrk Kinases
chemical_list: D002219:Carbamates; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D048493:Proto-Oncogene Proteins B-raf; D016160:Retinoblastoma Protein; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D000097603:Dyrk Kinases; C530104:CCND1 protein, human; C436291:CDKN1B protein, human; C000601108:encorafenib; C546842:MTOR protein, human; C482119:BRAF protein, human; C000605506:GSK3B protein, human
keywords: Autophagy; BRAF; Encorafenib (LGX818); Melanoma; Senescence