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Series GSE211052 Query DataSets for GSE211052
Status Public on Aug 15, 2022
Title Metabolic adaptations underpin resistance to histone acetyltransferase inhibition [QUANTseq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Histone acetyltransferases (HAT) catalyze the acylation of lysine side chains and are implicated in diverse human cancers as both oncogenes and non-oncogene dependencies. Acetyl-CoA-competitive HAT inhibitors have garnered attention as potential cancer therapeutics and the first clinical trial for this class is ongoing (NCT04606446). Despite broad enthusiasm for these targets, notably including CBP/p300 and KAT6A/B, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Using comparative transcriptional genomics, we found that the direct gene regulatory consequences of CBP/p300 HAT inhibition are indistinguishable in models of intrinsically hypersensitive and insensitive acute myeloid leukemia (AML). We therefore modelled acquired drug resistance using a forward genetic selection and identified dysregulation of coenzyme A (CoA) metabolism as a facile driver of resistance to HAT inhibitors. Specifically, drug resistance selected for mutations in PANK3, a pantothenate kinase that controls the rate limiting step in CoA biosynthesis. These mutations prevent negative feedback inhibition, resulting in drastically elevated concentrations of intracellular acetyl-CoA, which directly outcompetes drug-target engagement. This not only impacts the activity of structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B inhibitor that is currently in Phase-1 clinical trials. We further validated these results using a genome-scale CRISPR/Cas9 loss-of-function genetic modifier screen, which identified additional gene-drug interactions between HAT inhibitors and the CoA biosynthetic pathway. Top hits from the screen included the phosphatase, PANK4, which negatively regulates CoA production and therefore suppresses sensitivity to HAT inhibition upon knockout, as well as the pantothenate transporter, SLC5A6, which enhances sensitivity. Altogether, this work uncovers CoA plasticity as an unexpected but potentially class-wide liability of anti-cancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.
 
Overall design 3'-mRNA sequencing of a panel of AML cell lines following CBP/p300 HAT inhibition.
 
Contributor(s) Bishop T, Erb M
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Submission date Aug 11, 2022
Last update date Aug 15, 2022
Contact name Michael Erb
E-mail(s) michaelerb@scripps.edu
Phone 858-784-7034
Organization name The Scripps Research Institute
Department Department of Chemistry
Street address 10650 N Torrey Pines Rd
City La Jolla
State/province CA
ZIP/Postal code 92037
Country USA
 
Platforms (2)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (42)
GSM6448439 HL60_DMSO_QS_R1
GSM6448440 HL60_DMSO_QS_R2
GSM6448441 HL60_DMSO_QS_R3
This SubSeries is part of SuperSeries:
GSE211054 Metabolic adaptations underpin resistance to histone acetyltransferase inhibition
Relations
BioProject PRJNA868739

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE211052_MOLM13_WTand2R_QS_supptable.txt.gz 1.0 Mb (ftp)(http) TXT
GSE211052_QuantSeq_SuppTable.txt.gz 3.1 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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