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

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 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.This article is highlighted in the In This Issue feature, p. 305.

SUBMITTER: Ojha R

PROVIDER: S-EPMC6397701 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Ojha Rani R Leli Nektaria M NM Onorati Angelique A Piao Shengfu S Verginadis Ioannis I II Tameire Feven F Rebecca Vito W VW Chude Cynthia I CI Murugan Sengottuvelan S Fennelly Colin C Noguera-Ortega Estela E Chu Charleen T CT Liu Shujing S Xu Xiaowei X Krepler Clemens C Xiao Min M Xu Wei W Wei Zhi Z Frederick Dennie T DT Boland Genevieve G Mitchell Tara C TC Karakousis Giorgos C GC Schuchter Lynn M LM Flaherty Keith T KT Zhang Gao G Herlyn Meenhard M Koumenis Constantinos C Amaravadi Ravi K RK

Cancer discovery 20181218 3

Resistance to BRAF and MEK inhibitors (BRAFi + MEKi) in <i>BRAF</i>-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 <i>BRAF</i>-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 reactivat ...[more]

PMID: 30563872

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Project description:Therapies targeting oncogene addiction have had a tremendous impact on tumor growth and patient outcome, but drug resistance continues to be problematic. One approach to deal with the challenge of resistance entails extending anticancer treatments beyond targeting cancer cells by additionally altering the tumor microenvironment. Understanding how the tumor microenvironment contributes to the evolution of diverse resistance pathways could aid in the design of sequential treatments that can elicit and take advantage of a predictable resistance trajectory. Tumor-associated macrophages often support neoplastic growth and are frequently the most abundant immune cell found in tumors. Here, we used clinically relevant in vivo Braf-mutant melanoma models with fluorescent markers to track the stage-specific changes in macrophages under targeted therapy with Braf/Mek inhibitors and assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ monocyte-derived macrophage infiltration rose, suggesting that macrophage influx at this point could facilitate the onset of stable drug resistance that melanoma cells show after several weeks of treatment. Comparison of melanomas that develop in a Ccr2-proficient or -deficient microenvironment demonstrated that lack of melanoma infiltrating Ccr2+ macrophages delayed onset of resistance and shifted melanoma cell evolution towards unstable resistance. Unstable resistance was characterized by sensitivity to targeted therapy when factors from the microenvironment were lost. Importantly, this phenotype was reversed by coculturing melanoma cells with Ccr2+ macrophages. Overall, this study demonstrates that the development of resistance may be directed by altering the tumor microenvironment to improve treatment timing and the probability of relapse.SignificanceCcr2+ melanoma macrophages that are active in tumors during the drug-tolerant persister state following targeted therapy-induced regression are key contributors directing melanoma cell reprogramming toward specific therapeutic resistance trajectories.

Dataset Information

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

Publications

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

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