ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma.


Journal Article

Resistance to BRAF and MEK inhibitors (BRAFi + MEKi) in BRAF-mutant tumors occurs through heterogeneous mechanisms, including ERK reactivation and autophagy. Little is known about the mechanisms by which ERK reactivation or autophagy is induced by BRAFi + MEKi. Here, we report that in BRAF-mutant melanoma cells, BRAFi + MEKi induced SEC61-dependent endoplasmic reticulum (ER) translocation of the MAPK pathway via GRP78 and KSR2. Inhibition of ER translocation prevented ERK reactivation and autophagy. Following ER translocation, ERK exited the ER and was rephosphorylated by PERK. Reactivated ERK phosphorylated ATF4, which activated cytoprotective autophagy. Upregulation of GRP78 and phosphorylation of ATF4 were detected in tumors of patients resistant to BRAFi + MEKi. ER translocation of the MAPK pathway was demonstrated in therapy-resistant patient-derived xenografts. Expression of a dominant-negative ATF4 mutant conferred sensitivity to BRAFi + MEKi in vivo. This mechanism reconciles two major targeted therapy resistance pathways and identifies druggable targets, whose inhibition would likely enhance the response to BRAFi + MEKi. SIGNIFICANCE: ERK reactivation and autophagy are considered distinct resistance pathways to BRAF + MEK inhibition (BRAFi + MEKi) in BRAFV600E cancers. Here, we report BRAFi + MEKi-induced ER translocation of the MAPK pathway is necessary for ERK reactivation, which drives autophagy. The ER translocation mechanism is a major druggable driver of resistance to targeted therapy.This article is highlighted in the In This Issue feature, p. 305.

Full Text

Duke Authors

Cited Authors

  • Ojha, R; Leli, NM; Onorati, A; Piao, S; Verginadis, II; Tameire, F; Rebecca, VW; Chude, CI; Murugan, S; Fennelly, C; Noguera-Ortega, E; Chu, CT; Liu, S; Xu, X; Krepler, C; Xiao, M; Xu, W; Wei, Z; Frederick, DT; Boland, G; Mitchell, TC; Karakousis, GC; Schuchter, LM; Flaherty, KT; Zhang, G; Herlyn, M; Koumenis, C; Amaravadi, RK

Published Date

  • March 2019

Published In

Volume / Issue

  • 9 / 3

Start / End Page

  • 396 - 415

PubMed ID

  • 30563872

Pubmed Central ID

  • 30563872

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-18-0348


  • eng

Conference Location

  • United States