Open AccessTargeting CDK 2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors
Author(s) -
Azimi Alireza,
Caramuta Stefano,
SeashoreLudlow Brinton,
Boström Johan,
Robinson Jonathan L,
Edfors Fredrik,
Tuominen Rainer,
Kemper Kristel,
Krijgsman Oscar,
Peeper Daniel S,
Nielsen Jens,
Hansson Johan,
Egyhazi Brage Suzanne,
Altun Mikael,
Uhlen Mathias,
Maddalo Gianluca
Publication year - 2018
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.20177858
Subject(s) - biology , cyclin dependent kinase , hsp90 , melanoma , cancer research , cancer , cell cycle , genetics , heat shock protein , gene
Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL 888, 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 XL 888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK 2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL 888 treatment. The CDK 2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK 2 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.