ArticleMolecular cancer research : MCR2014
PP6C hotspot mutations in melanoma display sensitivity to Aurora kinase inhibition.
Article in Molecular cancer research : MCR, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 38 citations in OpenAlex.
- Functional Role of Protein Phosphatase-6 (Current medicinal chemistry · 2025Review
- Protein phosphatase 6 activates NF-κB to confer sensitivity to MAPK pathway inhibitors inScience signaling · 2024Article
- A multiparameter liquid biopsy approach allows to track melanoma dynamics and identify early treatment resistance.NPJ precision oncology · 2024Article
- Identification of Novel Candidate Genes for Familial Thyroid Cancer by Whole Exome Sequencing.International journal of molecular sciences · 2023Article
- Inducible protein degradation as a strategy to identify Phosphoprotein Phosphatase 6 substrates in RAS-mutant colorectal cancer cells.bioRxiv : the preprint server for biology · 2023Article
- Targeting the transcription factor HES1 by L-menthol restores protein phosphatase 6 in keratinocytes in models of psoriasis.Nature communications · 2022Article
- PPP6C, a serine-threonine phosphatase, regulates melanocyte differentiation and contributes to melanoma tumorigenesis through modulation of MITF activity.Scientific reports · 2022Article
- Dysregulated G2 phase checkpoint recovery pathway reduces DNA repair efficiency and increases chromosomal instability in a wide range of tumours.Oncogenesis · 2021Article
- PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK.Cell reports · 2021Article
- A Melanoma-Tailored Next-Generation Sequencing Panel Coupled with a Comprehensive Analysis to Improve Routine Melanoma Genotyping.Targeted oncology · 2020Article
- Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications.Frontiers in molecular biosciences · 2020Review
- ctDNA detected by ddPCR reveals changes in tumour load in metastatic malignant melanoma treated with bevacizumab.Scientific reports · 2019Article
- ANKRD44 Gene Silencing: A Putative Role in Trastuzumab Resistance in Her2-Like Breast Cancer.Frontiers in oncology · 2019Article
- Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Molecular Pathways in Melanomagenesis: What We Learned from Next-Generation Sequencing Approaches.Current oncology reports · 2018Review
- The multifaceted allosteric regulation of Aurora kinase A.The Biochemical journal · 2018Review
- A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation.eLife · 2018Article
- A water-mediated allosteric network governs activation of Aurora kinase A.Nature chemical biology · 2017Article
- CHK2-BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Review
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11 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledRecent whole genome melanoma sequencing studies have identified recurrent mutations in the gene encoding the catalytic subunit of serine/threonine phosphatase 6 (PPP6C/PP6C). However, the biochemical, functional, and clinical ramifications of these mutations are unknown. Sequencing PP6C from patients with melanoma (233 primary and 77 metastatic specimens) with extended prospective clinical outcome revealed a large number of hotspot mutations in patients with both primary and metastatic melanoma. Despite minimal association between stage and presence of PP6C mutations in patients with primary melanoma, a subpopulation of cells within each tumor did contain PP6C mutations, suggesting PP6C mutation is an early, but non-tumor-initiating event in melanoma. Among patients with primary melanoma with PP6C mutations, patients with stop mutations had significantly shorter recurrence-free survival compared with patients without stop mutations. In addition, PP6C mutations were independent of commonly observed BRAF and NRAS mutations. Biochemically, PP6C mutations could be classified as those that interact with PP6C regulatory subunits and those that do not. Mutations that did not bind to PP6C regulatory subunits were associated with increased phosphorylation of Aurora kinase, a PP6C substrate, and mitotic defects. However, both classes of PP6C mutations led to increased sensitivity to Aurora kinase inhibition. Together, these data support for the first time that PP6C mutations are molecularly, biochemically, and clinically heterogeneous. IMPLICATIONS: PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors.
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