PXD013988

PXD013988 is an original dataset announced via ProteomeXchange.

Title	HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma
Description	Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used multi-omics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance. Experimental Design: Mass spectrometry-based proteomics and RNA-Seq was used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo xenograft models of uveal melanoma. Results: We identified a number of putative escape pathways that were upregulated following MEK inhibition including the PI3K/AKT pathway, ROR1/2 and IGF1R signaling. MEK inhibition was also associated with a widespread increase in GPCR expression, particularly the Endothelin B receptor and that this contributed to therapeutic escape through YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo xenograft studies revealed the MEK-HDAC inhibitor combination to outperform either agent alone, leading to a long-term decrease of tumor growth and the suppression of adaptive PI3K/AKT and YAP signaling. Conclusions Together our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in uveal melanoma.
HostingRepository	PRIDE
AnnounceDate	2020-05-26
AnnouncementXML	Submission_2020-05-26_13:28:25.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD013988
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Biotin:Thermo-88310; Oxidation; Carbamidomethyl
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-05-23 07:27:24	ID requested
⏵ 1	2020-05-26 13:28:26	announced

Fai, ã, o-Flores F, Emmons MF, Durante MA, Kinose F, Saha B, Fang B, Koomen JM, Chellappan SP, Maria-Engler SS, Rix U, Licht JD, Harbour JW, Smalley KSM, Efficacy of MEK Inhibitor Therapy in Uveal Melanoma. Clin Cancer Res, 25(18):5686-5701(2019) [pubmed]

submitter keyword: ABPP, HDAC, uveal melanoma

Keiran Smalley, PhD
contact affiliation	Moffitt Cancer Center Tampa, FL, USA
contact email	keiran.smalley@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013988
     1. Label: PRIDE project
     2. Name: HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma