Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors

• Published in: Molecular systems biology Vol. 14; no. 3; pp. e7858 - n/a
• Main Authors: Azimi, Alireza, Caramuta, Stefano, Seashore‐Ludlow, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.03.2018; John Wiley and Sons Inc; Springer Nature
• Subjects: CDK2; EMBO03; EMBO17; EMBO31; Hsp90 and BRAF inhibitors; Medicin och hälsovetenskap; melanoma; MITF; proteomics; melanoma; MITF; proteomics; Hsp90 and BRAF inhibitors; CDK2
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.20177858

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. Synopsis Proteomics and phosphoproteomics analyses in melanoma cells identify CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors. Its expression is regulated by the transcription factor MITF and dinaciclib, a CDK2 inhibitor, overcomes the resistance to both classes of inhibitors. Proteome and phosphoproteome profiles of resistant versus sensitive melanoma cell lines were compared upon BRAFi, Hsp90i and combination thereof. Hsp90i resistance is driven by CDK2 upregulation, mediated by MITF, in melanoma cells. CDK2i, i.e. dinaciclib, overcomes BRAFi and Hsp90i resistance in melanoma cells. Graphical Abstract Proteomics and phosphoproteomics analyses in melanoma cells identify CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors. Its expression is regulated by the transcription factor MITF and dinaciclib, a CDK2 inhibitor, overcomes the resistance to both classes of inhibitors.