PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas

Hezhe Lu, Shujing Liu, Gao Zhang, Bin Wu, Yueyao Zhu, Dennie T. Frederick, Yi Hu, Wenqun Zhong, Sergio Randell, Norah Sadek, Wei Zhang, Gang Chen, Chaoran Cheng, Jingwen Zeng, Lawrence W. Wu, Jie Zhang, Xiaoming Liu, Wei Xu, Clemens Krepler, Katrin Sproesser & 21 others Min Xiao, Benchun Miao, Jianglan Liu, Claire D. Song, Jephrey Y. Liu, Giorgos C. Karakousis, Lynn M. Schuchter, Yiling Lu, Gordon Mills, Yusheng Cong, Jonathan Chernoff, Jun Guo, Genevieve M. Boland, Ryan J. Sullivan, Zhi Wei, Jeffrey Field, Ravi K. Amaravadi, Keith T. Flaherty, Meenhard Herlyn, Xiaowei Xu, Wei Guo

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi and MEKi) therapies have markedly improved the clinical outcomes of patients with metastatic melanoma. Unfortunately, the efficacy of these treatments is often countered by the acquisition of drug resistance1-6. Here we investigated the molecular mechanisms that underlie acquired resistance to BRAFi and to the combined therapy. Consistent with previous studies, we show that resistance to BRAFi is mediated by ERK pathway reactivation. Resistance to the combined therapy, however, is mediated by mechanisms independent of reactivation of ERK in many resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in cells with acquired drug resistance and have a pivotal role in mediating resistance. Our screening, using a reverse-phase protein array, revealed distinct mechanisms by which PAKs mediate resistance to BRAFi and the combined therapy. In BRAFi-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK. In cells that are resistant to the combined therapy, PAKs regulate JNK and β-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide insights into the molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.

Original languageEnglish (US)
Pages (from-to)133-136
Number of pages4
JournalNature
Volume550
Issue number7674
DOIs
StatePublished - Oct 5 2017
Externally publishedYes

Fingerprint

p21-Activated Kinases
Drug Resistance
Melanoma
Mitogen-Activated Protein Kinase Kinases
Therapeutics
Catenins
Protein Array Analysis
MAP Kinase Signaling System
Pharmaceutical Preparations
Phosphorylation
Apoptosis
Cell Line

ASJC Scopus subject areas

  • General

Cite this

Lu, H., Liu, S., Zhang, G., Wu, B., Zhu, Y., Frederick, D. T., ... Guo, W. (2017). PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. Nature, 550(7674), 133-136. https://doi.org/10.1038/nature24040

PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. / Lu, Hezhe; Liu, Shujing; Zhang, Gao; Wu, Bin; Zhu, Yueyao; Frederick, Dennie T.; Hu, Yi; Zhong, Wenqun; Randell, Sergio; Sadek, Norah; Zhang, Wei; Chen, Gang; Cheng, Chaoran; Zeng, Jingwen; Wu, Lawrence W.; Zhang, Jie; Liu, Xiaoming; Xu, Wei; Krepler, Clemens; Sproesser, Katrin; Xiao, Min; Miao, Benchun; Liu, Jianglan; Song, Claire D.; Liu, Jephrey Y.; Karakousis, Giorgos C.; Schuchter, Lynn M.; Lu, Yiling; Mills, Gordon; Cong, Yusheng; Chernoff, Jonathan; Guo, Jun; Boland, Genevieve M.; Sullivan, Ryan J.; Wei, Zhi; Field, Jeffrey; Amaravadi, Ravi K.; Flaherty, Keith T.; Herlyn, Meenhard; Xu, Xiaowei; Guo, Wei.

In: Nature, Vol. 550, No. 7674, 05.10.2017, p. 133-136.

Research output: Contribution to journalArticle

Lu, H, Liu, S, Zhang, G, Wu, B, Zhu, Y, Frederick, DT, Hu, Y, Zhong, W, Randell, S, Sadek, N, Zhang, W, Chen, G, Cheng, C, Zeng, J, Wu, LW, Zhang, J, Liu, X, Xu, W, Krepler, C, Sproesser, K, Xiao, M, Miao, B, Liu, J, Song, CD, Liu, JY, Karakousis, GC, Schuchter, LM, Lu, Y, Mills, G, Cong, Y, Chernoff, J, Guo, J, Boland, GM, Sullivan, RJ, Wei, Z, Field, J, Amaravadi, RK, Flaherty, KT, Herlyn, M, Xu, X & Guo, W 2017, 'PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas', Nature, vol. 550, no. 7674, pp. 133-136. https://doi.org/10.1038/nature24040
Lu H, Liu S, Zhang G, Wu B, Zhu Y, Frederick DT et al. PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. Nature. 2017 Oct 5;550(7674):133-136. https://doi.org/10.1038/nature24040
Lu, Hezhe ; Liu, Shujing ; Zhang, Gao ; Wu, Bin ; Zhu, Yueyao ; Frederick, Dennie T. ; Hu, Yi ; Zhong, Wenqun ; Randell, Sergio ; Sadek, Norah ; Zhang, Wei ; Chen, Gang ; Cheng, Chaoran ; Zeng, Jingwen ; Wu, Lawrence W. ; Zhang, Jie ; Liu, Xiaoming ; Xu, Wei ; Krepler, Clemens ; Sproesser, Katrin ; Xiao, Min ; Miao, Benchun ; Liu, Jianglan ; Song, Claire D. ; Liu, Jephrey Y. ; Karakousis, Giorgos C. ; Schuchter, Lynn M. ; Lu, Yiling ; Mills, Gordon ; Cong, Yusheng ; Chernoff, Jonathan ; Guo, Jun ; Boland, Genevieve M. ; Sullivan, Ryan J. ; Wei, Zhi ; Field, Jeffrey ; Amaravadi, Ravi K. ; Flaherty, Keith T. ; Herlyn, Meenhard ; Xu, Xiaowei ; Guo, Wei. / PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. In: Nature. 2017 ; Vol. 550, No. 7674. pp. 133-136.
@article{74c666ed197e409ea7034a01953d776a,
title = "PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas",
abstract = "Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi and MEKi) therapies have markedly improved the clinical outcomes of patients with metastatic melanoma. Unfortunately, the efficacy of these treatments is often countered by the acquisition of drug resistance1-6. Here we investigated the molecular mechanisms that underlie acquired resistance to BRAFi and to the combined therapy. Consistent with previous studies, we show that resistance to BRAFi is mediated by ERK pathway reactivation. Resistance to the combined therapy, however, is mediated by mechanisms independent of reactivation of ERK in many resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in cells with acquired drug resistance and have a pivotal role in mediating resistance. Our screening, using a reverse-phase protein array, revealed distinct mechanisms by which PAKs mediate resistance to BRAFi and the combined therapy. In BRAFi-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK. In cells that are resistant to the combined therapy, PAKs regulate JNK and β-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide insights into the molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.",
author = "Hezhe Lu and Shujing Liu and Gao Zhang and Bin Wu and Yueyao Zhu and Frederick, {Dennie T.} and Yi Hu and Wenqun Zhong and Sergio Randell and Norah Sadek and Wei Zhang and Gang Chen and Chaoran Cheng and Jingwen Zeng and Wu, {Lawrence W.} and Jie Zhang and Xiaoming Liu and Wei Xu and Clemens Krepler and Katrin Sproesser and Min Xiao and Benchun Miao and Jianglan Liu and Song, {Claire D.} and Liu, {Jephrey Y.} and Karakousis, {Giorgos C.} and Schuchter, {Lynn M.} and Yiling Lu and Gordon Mills and Yusheng Cong and Jonathan Chernoff and Jun Guo and Boland, {Genevieve M.} and Sullivan, {Ryan J.} and Zhi Wei and Jeffrey Field and Amaravadi, {Ravi K.} and Flaherty, {Keith T.} and Meenhard Herlyn and Xiaowei Xu and Wei Guo",
year = "2017",
month = "10",
day = "5",
doi = "10.1038/nature24040",
language = "English (US)",
volume = "550",
pages = "133--136",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7674",

}

TY - JOUR

T1 - PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas

AU - Lu, Hezhe

AU - Liu, Shujing

AU - Zhang, Gao

AU - Wu, Bin

AU - Zhu, Yueyao

AU - Frederick, Dennie T.

AU - Hu, Yi

AU - Zhong, Wenqun

AU - Randell, Sergio

AU - Sadek, Norah

AU - Zhang, Wei

AU - Chen, Gang

AU - Cheng, Chaoran

AU - Zeng, Jingwen

AU - Wu, Lawrence W.

AU - Zhang, Jie

AU - Liu, Xiaoming

AU - Xu, Wei

AU - Krepler, Clemens

AU - Sproesser, Katrin

AU - Xiao, Min

AU - Miao, Benchun

AU - Liu, Jianglan

AU - Song, Claire D.

AU - Liu, Jephrey Y.

AU - Karakousis, Giorgos C.

AU - Schuchter, Lynn M.

AU - Lu, Yiling

AU - Mills, Gordon

AU - Cong, Yusheng

AU - Chernoff, Jonathan

AU - Guo, Jun

AU - Boland, Genevieve M.

AU - Sullivan, Ryan J.

AU - Wei, Zhi

AU - Field, Jeffrey

AU - Amaravadi, Ravi K.

AU - Flaherty, Keith T.

AU - Herlyn, Meenhard

AU - Xu, Xiaowei

AU - Guo, Wei

PY - 2017/10/5

Y1 - 2017/10/5

N2 - Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi and MEKi) therapies have markedly improved the clinical outcomes of patients with metastatic melanoma. Unfortunately, the efficacy of these treatments is often countered by the acquisition of drug resistance1-6. Here we investigated the molecular mechanisms that underlie acquired resistance to BRAFi and to the combined therapy. Consistent with previous studies, we show that resistance to BRAFi is mediated by ERK pathway reactivation. Resistance to the combined therapy, however, is mediated by mechanisms independent of reactivation of ERK in many resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in cells with acquired drug resistance and have a pivotal role in mediating resistance. Our screening, using a reverse-phase protein array, revealed distinct mechanisms by which PAKs mediate resistance to BRAFi and the combined therapy. In BRAFi-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK. In cells that are resistant to the combined therapy, PAKs regulate JNK and β-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide insights into the molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.

AB - Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi and MEKi) therapies have markedly improved the clinical outcomes of patients with metastatic melanoma. Unfortunately, the efficacy of these treatments is often countered by the acquisition of drug resistance1-6. Here we investigated the molecular mechanisms that underlie acquired resistance to BRAFi and to the combined therapy. Consistent with previous studies, we show that resistance to BRAFi is mediated by ERK pathway reactivation. Resistance to the combined therapy, however, is mediated by mechanisms independent of reactivation of ERK in many resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in cells with acquired drug resistance and have a pivotal role in mediating resistance. Our screening, using a reverse-phase protein array, revealed distinct mechanisms by which PAKs mediate resistance to BRAFi and the combined therapy. In BRAFi-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK. In cells that are resistant to the combined therapy, PAKs regulate JNK and β-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide insights into the molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.

UR - http://www.scopus.com/inward/record.url?scp=85030770531&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030770531&partnerID=8YFLogxK

U2 - 10.1038/nature24040

DO - 10.1038/nature24040

M3 - Article

VL - 550

SP - 133

EP - 136

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7674

ER -