TY - JOUR
T1 - Er translocation of the mapk pathway drives therapy resistance in BRAF-mutant melanoma
AU - Ojha, Rani
AU - Leli, Nektaria M.
AU - Onorati, Angelique
AU - Piao, Shengfu
AU - Verginadis, Ioannis I.
AU - Tameire, Feven
AU - Rebecca, Vito W.
AU - Chude, Cynthia I.
AU - Murugan, Sengottuvelan
AU - Fennelly, Colin
AU - Noguera-Ortega, Estela
AU - Liu, Shujing
AU - Xu, Xiaowei
AU - Krepler, Clemens
AU - Xiao, Min
AU - Xu, Wei
AU - Wei, Zhi
AU - Frederick, Dennie T.
AU - Boland, Genevieve
AU - Mitchell, Tara C.
AU - Karakousis, Giorgos C.
AU - Schuchter, Lynn M.
AU - Flaherty, Keith T.
AU - Zhang, Gao
AU - Herlyn, Meenhard
AU - Koumenis, Constantinos
AU - Amaravadi, Ravi K.
N1 - Funding Information:
G. Boland reports receiving a commercial research grant from Takeda Oncology and honoraria from the speakers’ bureau of Novartis. T.C. Mitchell is a consultant/advisory board member for Merck, BMS, Incyte, and Aduro. K.T. Flaherty reports receiving a commercial research grant from Novartis; reports receiving commercial research support from Genentech and Array BioPharma; and is a consultant/advisory board member for Array BioPharma, Novartis, and Genentech. C. Koumenis reports receiving honoraria from the speakers’ bureaus of Hokkaido University, Japan, and MD Anderson Cancer Center. R.K. Amaravadi has ownership interest (including stock, patents, etc.) in Immunaccell and Pinpoint Therapeutics and is a consultant/advisory board member for Sprint Biosciences. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This work was supported by NIH grants R01CA169134, P01 CA114046, P01 CA165997, P30 CA016520, SPORE P50 CA174523, and 1R01CA198015. We would like to thank Charleen T. Chu (Veterans Affairs Pittsburgh Healthcare System, Pennsylvania) for providing ERK2-KD and ERK2-WT plasmids.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-18-0348
DO - 10.1158/2159-8290.CD-18-0348
M3 - Article
C2 - 30563872
AN - SCOPUS:85063594372
SN - 2159-8274
VL - 9
SP - 396
EP - 415
JO - Cancer Discovery
JF - Cancer Discovery
IS - 3
ER -