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A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [HOXC10]

ABSTRACT: HOXC10 overexpression modifies the therapeutic response to combined MEK and BRD4 inhibitors We performed microarray analysis of cells expressing LACZ or HOXC10 treated with MEK and BRD4 inhibition in combination for 24 hours, prior to the induction of cell death, to analyze transcriptional changes that might be mechanistic drivers of the therapeutic effect.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118908 | GEO | 2020/04/02

REPOSITORIES: GEO

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HOXC10 overexpression modifies the therapeutic response to combined MEK and BRD4 inhibitors

Project description:We performed microarray analysis of cells expressing LACZ or HOXC10 treated with MEK and BRD4 inhibition in combination for 24 hours, prior to the induction of cell death, to analyze transcriptional changes that might be mechanistic drivers of the therapeutic effect. 12 samples in triplicate, 3X LACZ + vehicle treatment, 3X HOXC10 + vehicle treatment, 3X LACZ + combo treatment, 3X HOXC10 + combo treatment

2021-09-02 | E-MTAB-7181 | biostudies-arrayexpress

A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [inhibitors]

Project description:MEK and BRD4 inhibitors induce cell death of subset of KRAS-mutant lung tumors in vitro and in vivo We performed microarray analysis of MEK and BRD4 inhibition alone and in combination 24 hours after treatment, prior to the induction of cell death, to analyze transcriptional changes that might be mechanistic drivers of the therapeutic effect

2020-04-02 | GSE118903 | GEO

A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [HOXC10]

Project description:A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [HOXC10]

| PRJNA487268 | ENA

A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-04-02 | GSE118909 | GEO

MEK and BRD4 inhibitors induce cell death of subset of KRAS-mutant lung tumors in vitro and in vivo

Project description:We performed microarray analysis of MEK and BRD4 inhibition alone and in combination 24 hours after treatment, prior to the induction of cell death, to analyze transcriptional changes that might be mechanistic drivers of the therapeutic effect

2021-09-02 | E-MTAB-7180 | biostudies-arrayexpress

A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers

Project description:A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers

| PRJNA487264 | ENA

Regulatory integration of Hox factor action with Tbox factors in limb development

Project description:Hindlimb and Forelimb-specific Tbox factors integrates their mode of action with distinct Hox factors resulting in different transcriptional outcomes. In addition, hindlimb-specific Tbx4, Hoxc10 and Pitx1 act on the same platform to target common putative downstream genes for hindlimb development

2018-03-08 | GSE104398 | GEO

A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [inhibitors]

Project description:A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [inhibitors]

| PRJNA487269 | ENA

Intrinsic Resistance to MEK Inhibition Through BET Protein Mediated Kinome

Project description:Mutation or deletion of Neurofibromin (NF1), an inhibitor of RAS signaling, frequently occurs in epithelial ovarian cancer (EOC), supporting therapies that target downstream RAS effectors, such as the RAF-MEK-ERK pathway. However, no comprehensive studies have been carried out testing the efficacy of MEK inhibition in NF1-deficient EOC. Here, we performed a detailed characterization of MEK inhibition in NF1-deficient EOC cell lines using kinome profiling and RNA sequencing. Our studies showed MEK inhibitors were ineffective at providing durable growth inhibition in NF1-deficient cells due to kinome reprogramming. MEKi-mediated destabilization of FOSL1 resulted in induced expression of RTKs and their downstream RAF and PI3K signaling overcoming MEKi therapy. MEKi synthetic enhancement screens identified BRD2 and BRD4 as integral mediators of the MEKi-induced RTK signatures. Inhibition of BET proteins using BET bromodomain inhibitors (BETi) blocked MEKi-induced RTK reprogramming, indicating BRD2 and BRD4 represent promising therapeutic targets in combination with MEKi to block resistance due to kinome reprogramming in NF1-deficient EOC.

2019-05-17 | GSE127886 | GEO

A deregulated m<sup>6</sup>A writer complex axis driven by BRD4 confers an epitranscriptomic vulnerability in combined DNA repair-targeted therapy.

Project description:Aberrant transcripts expression of the m6A methyltransferase complex (MTC) is widely found across human cancers, suggesting a dysregulated signaling cascade which integrates m6A epitranscriptome to drive tumorigenesis. However, the responsible transcriptional machinery directing the expression of distinct MTC subunits remains unclear. Here, we identified an unappreciated interplay between the histone acetyl-lysine reader BRD4 and the m6A writer complex across human cancers. BRD4 directly stimulates transcripts expression of seven MTC subunits, allowing the maintenance of the nuclear writer complex integrity. Upon BET inhibition, this BRD4-MTC signaling cascade accounts for global m6A reduction and the subsequent dynamic alteration of BRD4-dependent transcriptome, resulting in impaired DNA damage response that involves activation of homologous recombination (HR) repair and repression of apoptosis. We further demonstrated that the combined synergy upon BET/PARP inhibition largely relies on disrupted m6A modification of HR and apoptotic genes, counteracting PARP inhibitor (PARPi) resistance in patient-derived xenograft models. Our study revealed a widespread active cross-talk between BRD4-dependent epigenetic and MTC-mediated epitranscriptomic networks, which provides a unique therapeutic vulnerability that can be leveraged in combined DNA repair-targeted therapy.

| S-EPMC10576145 | biostudies-literature

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