A research team led by Gianluca Maddalo (KTH), involving several researchers at SciLifeLab, has discovered that melanoma resistance against BRAF and Hsp90 inhibitors can be overcome by implementing the current BRAF/MEK inhibitors therapy with a CDK2 inhibitor, dinaciclib, already used in clinical trials.
Thermal proteome profiling (TPP) identified the protein targets of the Hsp90 inhibitor XL888 (currently used in clinical trials) in a pair of sensitive and unresponsive cell lines.
Proteomics and phosphoproteomics analyses in melanoma cells identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors. Its expression is regulated by the transcription factor MITF and dinaciclib attenuated the resistance to both classes of inhibitors and their combination.
Notably, they observed 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.
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