Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors
Artikel i vetenskaplig tidskrift, 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

Författare

Alireza Azimi

Karolinska universitetssjukhuset

Stefano Caramuta

Karolinska universitetssjukhuset

Brinton Seashore-Ludlow

Karolinska Institutet

Johan Boström

Karolinska Institutet

Jonathan Robinson

Chalmers, Biologi och bioteknik, Systembiologi

F. Edfors

Kungliga Tekniska Högskolan (KTH)

Rainer Tuominen

Karolinska universitetssjukhuset

Kristel Kemper

The Netherlands Cancer Institute

Oscar Krijgsman

The Netherlands Cancer Institute

Daniel S. Peeper

The Netherlands Cancer Institute

Jens B Nielsen

Chalmers, Biologi och bioteknik, Systembiologi

Johan Hansson

Karolinska universitetssjukhuset

Suzanne Egyhazi Brage

Karolinska universitetssjukhuset

Mikael Altun

Karolinska Institutet

Mathias Uhlen

Kungliga Tekniska Högskolan (KTH)

Gianluca Maddalo

Kungliga Tekniska Högskolan (KTH)

Molecular Systems Biology

1744-4292 (ISSN)

Vol. 14 3 e7858

Ämneskategorier

Cell- och molekylärbiologi

Hematologi

Cancer och onkologi

DOI

10.15252/msb.20177858