Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation

被引：54

作者：

Kim, Hyungsoo ^{[1
]}

Frederick, Dennie T. ^{[2
]}

Levesque, Mitchell P. ^{[3
,4
]}

Cooper, Zachary A. ^{[5
,6
]}

Feng, Yongmei ^{[1
]}

Krepler, Clemens ^{[7
]}

Brill, Laurence ^{[1
]}

Samuels, Yardena ^{[8
]}

Hayward, Nicholas K. ^{[9
]}

Perlina, Ally ^{[1
]}

Piris, Adriano ^{[2
]}

Zhang, Tongwu ^{[10
]}

Halaban, Ruth ^{[11
]}

Herlyn, Meenhard M.

Brown, Kevin M. ^{[10
]}

Wargo, Jennifer A. ^{[5
,6
]}

Dummer, Reinhard ^{[3
,4
]}

Flaherty, Keith T. ^{[2
]}

Ronai, Ze'ev A. ^{[1
]}

机构：

[1] Sanford Burnham Med Res Inst, Ctr Canc, La Jolla, CA 92037 USA

[2] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02114 USA

[3] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland

[4] Univ Zurich, CH-8091 Zurich, Switzerland

[5] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[7] Wistar Inst Anat & Biol, Melanoma Res Ctr, Philadelphia, PA 19104 USA

[8] Weizmann Inst Sci, IL-76100 Rehovot, Israel

[9] QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia

[10] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[11] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA

来源：

CELL REPORTS | 2015年 / 11卷 / 09期

关键词：

BRAF(V600E) INHIBITION; ACQUIRED-RESISTANCE; DRIVEN RESISTANCE; EGF RECEPTOR; CANCER; OVERCOME; VEMURAFENIB; DABRAFENIB; MUTATIONS; PATHWAYS;

D O I：

10.1016/j.celrep.2015.04.049

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription. Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases (RTKs), including EGFR. Notably, RNF125 altered RTK expression through JAK1, which we identified as an RNF125 substrate. RNF125 bound to and ubiquitinated JAK1, prompting its degradation and suppressing RTK expression. Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression, as shown in culture and in in vivo xenografts. Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression.

引用

页码：1458 / 1473

页数：16

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