| Autor: |
Alireza Azimi, Stefano Caramuta, Brinton Seashore‐Ludlow, Johan Boström, Jonathan L Robinson, Fredrik Edfors, Rainer Tuominen, Kristel Kemper, Oscar Krijgsman, Daniel S Peeper, Jens Nielsen, Johan Hansson, Suzanne Egyhazi Brage, Mikael Altun, Mathias Uhlen, Gianluca Maddalo |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Molecular Systems Biology, Vol 14, Iss 3, Pp 1-16 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
1744-4292 |
| DOI: |
10.15252/msb.20177858 |
| Popis: |
Abstract 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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