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Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors

Alireza Azimi1, Stefano Caramuta1, Brinton Seashore-Ludlow2

  • 1Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Molecular Systems Biology
|March 7, 2018
PubMed

Insights

The combination of XL888 (Hsp90 inhibitor) and BRAF inhibitors shows varied responses in melanoma. Cyclin-dependent kinase 2 (CDK2) drives resistance, suggesting CDK2 inhibitors like dinaciclib as a potential therapy for unresponsive patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Melanoma treatment resistance necessitates novel therapeutic strategies.
  • Hsp90 inhibitors (e.g., XL888) combined with BRAF inhibitors are under investigation for resistant melanomas.
  • Previous studies show heterogeneous responses to these combined therapies.

Purpose of the Study:

  • To elucidate the mechanisms behind differential responses to XL888 and BRAF inhibitor combinations in melanoma.
  • To identify biomarkers for patient stratification in therapy-resistant melanoma.
  • To explore potential therapeutic interventions targeting resistance mechanisms.

Main Methods:

  • Thermal proteome profiling (TPP) to identify XL888 protein targets.
  • Unbiased proteomics and phosphoproteomics analyses to uncover resistance drivers.
  • In vitro studies using melanoma cell lines and patient-derived xenograft (PDX) models.
  • Evaluation of CDK2 inhibitor (dinaciclib) efficacy in overcoming resistance.

Main Results:

  • TPP identified protein targets of XL888.
  • Cyclin-dependent kinase 2 (CDK2) was identified as a key driver of resistance to both BRAF and Hsp90 inhibitors.
  • CDK2 expression is regulated by MITF upon XL888 treatment.
  • The CDK2 inhibitor dinaciclib reversed resistance to BRAF and Hsp90 inhibitors.
  • MITF expression correlates with CDK2 upregulation in patients.

Conclusions:

  • CDK2 is a critical mediator of resistance to combined BRAF and Hsp90 inhibition in melanoma.
  • MITF regulates CDK2 expression, linking it to resistance.
  • Dinaciclib demonstrates potential as a therapeutic agent for melanoma patients unresponsive to current therapies, particularly those with MITF amplification or overexpression.
Keywords:
MITFCDK2Hsp90 and BRAF inhibitorsmelanomaproteomics

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