Dataset Information

CETSA Hsp90i - Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors

ABSTRACT: The goal of this project is to identify the drug target of XL888, an hsp90i used in clinical trial against melanoma

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Gianluca Maddalo

LAB HEAD: Mathias Uhlen

PROVIDER: PXD005508 | Pride | 2018-02-13

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	HF1_201501204_GM_RJ1511B_TMT10_hpHRP_SK28_DMSO1__2p5ug_5uL_fr01.mgf	Mgf
	HF1_201501204_GM_RJ1511B_TMT10_hpHRP_SK28_DMSO1__2p5ug_5uL_fr01.pride.mgf.gz	Mgf
	HF1_201501204_GM_RJ1511B_TMT10_hpHRP_SK28_DMSO1__2p5ug_5uL_fr01.pride.mztab.gz	Mztab
	HF1_201501204_GM_RJ1511B_TMT10_hpHRP_SK28_DMSO1__2p5ug_5uL_fr01.raw	Raw
	HF1_201501204_GM_RJ1511B_TMT10_hpHRP_SK28_DMSO1__2p5ug_5uL_fr01.xml.gz	Xml

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Publications

Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors.

Azimi Alireza A Caramuta Stefano S Seashore-Ludlow Brinton B Boström Johan J Robinson Jonathan L JL Edfors Fredrik F Tuominen Rainer R Kemper Kristel K Krijgsman Oscar O Peeper Daniel S DS Nielsen Jens J Hansson Johan J Egyhazi Brage Suzanne S Altun Mikael M Uhlen Mathias M Maddalo Gianluca G

Molecular systems biology 20180305 3

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 prote ...[more]

PMID: 29507054

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Project description:The two most common melanoma histopathologic subtypes, superficial spreading (SSM) and nodular melanoma (NM), are believed to represent sequential phases of linear progression from radial to vertical growth. Studies suggest, however, that SSM and NM are biologically distinct. We utilized an integrative genomic approach to examine the possibility that SSM and NM are the result of independent pathways characterized by unique molecular alterations. Cell lines including SSM, NM, metastatic melanoma, and melanocyte controls were evaluated for copy number changes and differential mRNA expression using single nucleotide polymorphism array (SNP 6.0, Affymetrix) and gene array (U133A 2.0, Affymetrix). Data sets were integrated to identify copy number alterations that correlated with gene expression, and array results were validated using immunohistochemistry on human tissue microarrays (TMAs) and an external data set. The functional effect of genomic deletion was assessed by lentiviral overexpression. Integrative genomics revealed 8 genes in which NM/SSM-specific copy number alterations were correlated with NM/SSM differential gene expression (P<0.05, Spearman’s rank). Pathways analysis of differentially expressed genes (N=114) showed enrichment for metabolic-related processes. SSM-specific genomic deletions (DIS3, MTAP, G3BP2, SEC23IP, USO1) were verified in an expanded panel of cell lines, and forced overexpression of MTAP in SSM resulted in reduced cell growth. Metabolism-related gene ALDH7A1 was verified as overexpressed in NM using human TMAs.The identification of recurrent genomic deletions in SSM not present in NM challenges the linear model of melanoma progression and supports the unique molecular classification of SSM and NM. Gene expression profiling using Affymetrix U133A 2.0 arrays was performed on 18 melanoma cell lines including 2 primary superficial spreading melanoma, 2 primary nodular melanoma, 2 metastatic nodular melanoma, and 12 metastatic cell lines. Four melanocyte control lines were also evaluated including 2 immortalized melanocyte cell lines (Hermes 1 and 2B) and 2 normal melanocyte lines cultured from neonatal foreskin (HEM-N and HEM-LP).