PXD033866

PXD033866 is an original dataset announced via ProteomeXchange.

Title	Effect of PTEN knockout on dabrafenib-trametinib treatment in A375 melanoma cells - replicate 1
Description	Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAFand MEK1/2 in PTEN null, BRAFV600E cells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with inhibitors for mutant BRAF/MEK1/2 identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600E cells. The findings indicate PTEN null BRAFV600E melanoma becomes dependent on ERBB/HER signaling when treated with clinically approved BRAF and MEK inhibitors. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:37:09.310.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Steven Angus
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-12 09:31:11	ID requested
1	2024-04-23 06:12:27	announced
⏵ 2	2024-10-22 06:37:09	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: A375, kinase inhibitor, BRAF,melanoma, MEK, kinome

Steven P Angus
contact affiliation	Deaprtment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202
contact email	sangus@iu.edu
lab head
Steven Angus
contact affiliation	Indiana University School of Medicine
contact email	sangus@iu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD033866
     1. Label: PRIDE project
     2. Name: Effect of PTEN knockout on dabrafenib-trametinib treatment in A375 melanoma cells - replicate 1