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Accepted (AM)Open Access (License Unspecified), Open
Letter/Communication
PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas
Nature (London), v 550(7674), pp 133-136
05 Oct 2017
PMID: 28953887
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 resistance. 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.
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Details
- Title
- PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas
- Creators
- Hezhe Lu - University of PennsylvaniaShujing Liu - Raymond and Ruth Perelman School of Medicine at the University of PennsylvaniaGao Zhang - The Wistar InstituteBin Wu - University of PennsylvaniaYueyao Zhu - University of PennsylvaniaDennie T Frederick - Massachusetts General HospitalYi Hu - Drexel UniversityWenqun Zhong - University of PennsylvaniaSergio Randell - The Wistar InstituteNorah Sadek - The Wistar InstituteWei Zhang - University of PennsylvaniaGang Chen - University of PennsylvaniaChaoran Cheng - New Jersey Institute of TechnologyJingwen Zeng - University of PennsylvaniaLawrence W Wu - The Wistar InstituteJie Zhang - New Jersey Institute of TechnologyXiaoming Liu - Raymond and Ruth Perelman School of Medicine at the University of PennsylvaniaWei Xu - Drexel University, Microbiology and ImmunologyClemens Krepler - The Wistar InstituteKatrin Sproesser - The Wistar InstituteMin Xiao - The Wistar InstituteBenchun Miao - Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USAJianglan Liu - The Wistar InstituteClaire D Song - University of PennsylvaniaJephrey Y Liu - Chinese Academy of SciencesGiorgos C Karakousis - Hospital of the University of PennsylvaniaLynn M Schuchter - Raymond and Ruth Perelman School of Medicine at the University of PennsylvaniaYiling Lu - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USAGordon Mills - Oregon Health & Science UniversityYusheng Cong - Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, ChinaJonathan Chernoff - Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USAJun Guo - Peking UniversityGenevieve M Boland - Massachusetts General HospitalRyan J Sullivan - Massachusetts General HospitalZhi Wei - New Jersey Institute of TechnologyJeffrey Field - Raymond and Ruth Perelman School of Medicine at the University of PennsylvaniaRavi K Amaravadi - Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USAKeith T Flaherty - Massachusetts General HospitalMeenhard Herlyn - The Wistar InstituteXiaowei Xu - University of PennsylvaniaWei Guo - University of Pennsylvania
- Publication Details
- Nature (London), v 550(7674), pp 133-136
- Publisher
- Springer Nature
- Number of pages
- 4
- Grant note
- R01 GM085146 / NIGMS NIH HHS CA142928 / NCI NIH HHS CA174523 / NCI NIH HHS R01 HL134923 / NHLBI NIH HHS CA025874 / NCI NIH HHS U54 CA193417 / NCI NIH HHS P01 CA025874 / NCI NIH HHS P01 CA114046 / NCI NIH HHS P30 CA010815 / NCI NIH HHS P50 CA174523 / NCI NIH HHS CA114046 / NCI NIH HHS
- Resource Type
- Letter/Communication
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000412214100060
- Scopus ID
- 2-s2.0-85030770531
- Other Identifier
- 991021867710704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology