SPRED1 deletion confers resistance to MAPK inhibition in melanoma

被引：23

作者：

Ablain, Julien ^{[1
,2
]}

Liu, Sixue ^{[3
,5
]}

Moriceau, Gatien ^{[3
,5
,6
]}

Lo, Roger S. ^{[3
,4
,5
,6
]}

Zon, Leonard, I ^{[1
,2
,7
,8
]}

机构：

[1] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Boston, MA 02115 USA

[3] Univ Calif Los Angeles, Dept Med, Div Dermatol, Los Angeles, CA 90024 USA

[4] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA

[7] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[8] Howard Hughes Med Inst, Boston, MA 02115 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2021年 / 218卷 / 03期

基金：

美国国家卫生研究院;

关键词：

LEGIUS SYNDROME; PROTEIN; BRAF; DOMAIN; NF1; VEMURAFENIB; EFFICACY; MUTANTS; ENCODES; PATHWAY;

D O I：

10.1084/jem.20201097

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Functional evaluation of genetic lesions can discover a role in cancer initiation and progression and help develop novel therapeutic strategies. We previously identified the negative MAPK regulator SPRED1 as a novel tumor suppressor in KIT-driven melanoma. Here, we show that SPRED1 is also frequently deleted in human melanoma driven by mutant BRAF. We found that SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAF(V600E) inhibition in vitro and in vivo. Mechanistically, SPRED1 loss promoted melanoma cell proliferation under mutant BRAF inhibition by reactivating MAPK activity. Consistently, biallelic deletion of SPRED1 was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy. These studies combining work in human cells and in vivo modeling in zebrafish demonstrate a new mechanism of resistance to BRAF(V600E) inhibition in melanoma.

引用

页数：14

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