Er translocation of the mapk pathway drives therapy resistance in BRAF-mutant melanoma
Document Type
Article
Publication Date
3-1-2019
Abstract
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 cyto-protective 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 ther-apy-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 BRAF V600E 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.
Identifier
85063594372 (Scopus)
Publication Title
Cancer Discovery
External Full Text Location
https://doi.org/10.1158/2159-8290.CD-18-0348
e-ISSN
21598290
ISSN
21598274
PubMed ID
30563872
First Page
396
Last Page
415
Issue
3
Volume
9
Grant
1R01CA198015
Fund Ref
National Institutes of Health
Recommended Citation
Ojha, Rani; Leli, Nektaria M.; Onorati, Angelique; Piao, Shengfu; Verginadis, Ioannis I.; Tameire, Feven; Rebecca, Vito W.; Chude, Cynthia I.; Murugan, Sengottuvelan; Fennelly, Colin; Noguera-Ortega, Estela; Liu, Shujing; Xu, Xiaowei; Krepler, Clemens; Xiao, Min; Xu, Wei; Wei, Zhi; Frederick, Dennie T.; and Boland, Genevieve, "Er translocation of the mapk pathway drives therapy resistance in BRAF-mutant melanoma" (2019). Faculty Publications. 7769.
https://digitalcommons.njit.edu/fac_pubs/7769
