Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors

Mol Syst Biol. 2018 Mar 5;14(3):e7858. doi: 10.15252/msb.20177858.

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.

Keywords: MITF; CDK2; Hsp90 and BRAF inhibitors; melanoma; proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azabicyclo Compounds / pharmacology*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism*
  • Drug Resistance, Neoplasm* / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • Humans
  • Imidazoles / pharmacology*
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Oximes / pharmacology*
  • Phosphoproteins / metabolism
  • Phthalic Acids / pharmacology*
  • Proteomics
  • Pyridinium Compounds / pharmacology
  • Up-Regulation

Substances

  • Azabicyclo Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • HSP90 Heat-Shock Proteins
  • Imidazoles
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • Oximes
  • Phosphoproteins
  • Phthalic Acids
  • Pyridinium Compounds
  • XL 888
  • dinaciclib
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • dabrafenib