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Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors
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2018 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 14, no 3, article id e7858Article in journal (Refereed) Published
Abstract [en]

Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF-MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression. 

Place, publisher, year, edition, pages
Blackwell Publishing Ltd , 2018. Vol. 14, no 3, article id e7858
Keywords [en]
CDK2, Hsp90 and BRAF inhibitors, melanoma, MITF, proteomics
National Category
Medical Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-227407DOI: 10.15252/msb.20177858ISI: 000429006500002Scopus ID: 2-s2.0-85044744573OAI: oai:DiVA.org:kth-227407DiVA, id: diva2:1210673
Note

Export Date: 9 May 2018; Article; Correspondence Address: Maddalo, G.; Science for Life Laboratory, School of Biotechnology, KTH Royal Institute of TechnologySweden; email: gianluca.maddalo@scilifelab.se; Funding details: IHC, Idaho Humanities Council; Funding details: 154202, Cancerfonden; Funding details: 5310-7132, O. E. och Edla Johanssons Vetenskapliga Stiftelse; Funding details: MTA, Mount Allison University; Funding text: We acknowledge Prof. Sonia Lain and Prof. David Lane and their groups for technical support and for granting us permission to access their Orbitrap Fusion. The cell line pairs M026.X1.CL and M026R.X1.CL, and M029.X1.CL and M029.R.X1.CL have been used according to the Material Transfer Agreement (MTA) for academic institutions V01 13 and V08 16, respectively. GM has been awarded grants from: O. E. och Edla Johanssons foundation (5310-7132); Swedish Cancer Society (Radiumhemmets; 154202); and Lars Hiertas Minne. The authors acknowledge the entire staff of the Protein Atlas Project for the IHC images. We acknowledge Prof. Janne Lehtiö and Rozbeh Jafari for support with TPP. QC 20180529

Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2018-05-29Bibliographically approved

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Uhlén, Mathias

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