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 SproesserMin 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

    63 Scopus citations

    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

    ASJC Scopus subject areas

    • General

    Fingerprint Dive into the research topics of 'PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas'. Together they form a unique fingerprint.

  • Cite this

    Lu, H., Liu, S., Zhang, G., Wu, B., Zhu, Y., Frederick, D. T., Hu, Y., Zhong, W., Randell, S., Sadek, N., Zhang, W., Chen, G., Cheng, C., Zeng, J., Wu, L. W., Zhang, J., Liu, X., Xu, W., Krepler, C., ... 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