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Cancer Discov. 2018 Dec 18. doi: 10.1158/2159-8290.CD-18-0348. [Epub ahead of print]

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

Author information

1
Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
2
Department of Radiation Oncology, Smilow Center for Translational Research, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
4
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania.
5
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey.
6
Massachusetts General Hospital, Harvard University, Boston, Massachusetts.
7
Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
8
Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Ravi.amaravadi@uphs.upenn.edu.

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 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.

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