Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors
Journal article, 2018

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.

melanoma

CDK2

proteomics

MITF

Hsp90 and BRAF inhibitors

Author

Alireza Azimi

Karolinska University Hospital

Stefano Caramuta

Karolinska University Hospital

Brinton Seashore-Ludlow

Karolinska Institutet

Johan Boström

Karolinska Institutet

Jonathan Robinson

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

F. Edfors

Royal Institute of Technology (KTH)

Rainer Tuominen

Karolinska University Hospital

Kristel Kemper

The Netherlands Cancer Institute

Oscar Krijgsman

The Netherlands Cancer Institute

Daniel S. Peeper

The Netherlands Cancer Institute

Jens B Nielsen

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Johan Hansson

Karolinska University Hospital

Suzanne Egyhazi Brage

Karolinska University Hospital

Mikael Altun

Karolinska Institutet

Mathias Uhlen

Royal Institute of Technology (KTH)

Gianluca Maddalo

Royal Institute of Technology (KTH)

Molecular Systems Biology

1744-4292 (ISSN)

Vol. 14 3 e7858

Subject Categories

Cell and Molecular Biology

Hematology

Cancer and Oncology

DOI

10.15252/msb.20177858

More information

Latest update

5/29/2018