Er translocation of the mapk pathway drives therapy resistance in BRAF-mutant melanoma

Rani Ojha, Nektaria M. Leli, Angelique Onorati, Shengfu Piao, Ioannis I. Verginadis, Feven Tameire, Vito W. Rebecca, Cynthia I. Chude, Sengottuvelan Murugan, Colin Fennelly, Estela Noguera-Ortega, Shujing Liu, Xiaowei Xu, Clemens Krepler, Min Xiao, Wei Xu, Zhi Wei, Dennie T. Frederick, Genevieve Boland, Tara C. MitchellGiorgos C. Karakousis, Lynn M. Schuchter, Keith T. Flaherty, Gao Zhang, Meenhard Herlyn, Constantinos Koumenis, Ravi K. Amaravadi

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)396-415
Number of pages20
JournalCancer Discovery
Issue number3
StatePublished - Mar 1 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology


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