Enhancer Remodeling During Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacological Targeting of the P-TEFb Complex
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PROVIDER: PRJNA344730 | ENA |
REPOSITORIES: ENA
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Project description:Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment. In preclinical models MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation and p300 that drives transcriptional adaptation. Inhibition of P-TEFb associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts and syngeneic mouse TNBC models. Pharmacological targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.
2017-01-20 | GSE87423 | GEO
Project description:Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment. In preclinical models MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation and p300 that drives transcriptional adaptation. Inhibition of P-TEFb associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts and syngeneic mouse TNBC models. Pharmacological targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.
2017-01-20 | GSE87419 | GEO
Project description:Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment. In preclinical models MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation and p300 that drives transcriptional adaptation. Inhibition of P-TEFb associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts and syngeneic mouse TNBC models. Pharmacological targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.
2017-01-20 | GSE87418 | GEO
Project description:Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment. In preclinical models MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation and p300 that drives transcriptional adaptation. Inhibition of P-TEFb associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts and syngeneic mouse TNBC models. Pharmacological targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.
2017-01-20 | GSE87154 | GEO
Project description:Enhancer Remodeling During Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacological Targeting of the P-TEFb Complex (RNA-seq)
| PRJNA344725 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-01-20 | GSE87424 | GEO
Project description:We showed that pharmacological inhibition of P-TEFb attenuated cyst development in ADPKD mouse models. Genome-wide analyses demonstrated that P-TEFb inhibition abrogated transcriptional pause release and suppressed a pathologic gene expression program during cystogenesis. This work revealed a mechanism by which aberrant activation of P-TEFb-mediated transcription elongation promotes cystogenesis in ADPKD.
2019-06-20 | GSE128522 | GEO
Project description:We showed that pharmacological inhibition of P-TEFb attenuated cyst development in ADPKD mouse models. Genome-wide analyses demonstrated that P-TEFb inhibition abrogated transcriptional pause release and suppressed a pathologic gene expression program during cystogenesis. This work revealed a mechanism by which aberrant activation of P-TEFb-mediated transcription elongation promotes cystogenesis in ADPKD.
2019-06-20 | GSE128521 | GEO
Project description:Triple negative breast cancer (TNBC) is heterogeneous with patients exhibiting at least two molecular subtypes, basal-like (BL) and claudin-low (CL). MEK inhibitor (MEKi) treatment of BL and CL cell lines and mouse model tumors induced subtype-specific alterations in overall kinome activity referred to as protein kinase reprogramming. BL- and CL-specific reprogramming involving increases in receptor tyrosine kinases was also seen in TNBC patients comparing tumor samples before and after a one week treatment with the MEKi, trametinib. Combination of kinase inhibitors targeted to the BL and CL reprogrammed signatures would need to be individually selected due to the heterogeneous resiliency of BL and CL kinomes. To overcome this “reprogramming dilemma” we targeted the transcriptional co-activator BRD4 with BET bromodomain inhibitors, JQI and IBET151; both strongly inhibited kinome reprogramming and onset of MEKi resistance in BL and CL cells. Targeting chromatin modifiers may therapeutically block resistance due to kinome reprogramming.BL and CL TNBC are commonly treated as a single disease despite genomic studies showing they represent distinct molecular subtypes1. Recent Cancer Genome Atlas data demonstrated that the 518 protein kinases in the human genome (the kinome) were infrequently mutated in BL breast cancer; however, EGFR, KRAS and BRAF were amplified in 22, 32 and 31% of BL tumors, respectively. These findings are consistent with frequent activation of the BRAF-MEK-ERK pathway in TNBC2,3 and inhibitors targeting kinases in this pathway are currently in clinical trials for TNBC. As single agents, targeted kinase inhibitors generally fail to sustain durable responses when used to treat a range of human cancers including TNBC4-6. Onset of kinase inhibitor resistance can be due to selection of mutations in the targeted kinase7,8, activating mutations or amplification of RAS or downstream kinases9,10 or kinome reprogramming, a process in which there are system-wide changes in kinase networks11-13. Each of these resistance mechanisms allows the cancer cell to circumvent the targeted inhibition of specific kinases14. We previously developed chemical, proteomic methods that assay the activation state of protein kinases en masse15,16. Our methods utilize ¬Multiplexed Inhibitor Beads (MIBs), mixtures of covalently immobilized, linker adapted, kinase inhibitors. The immobilized inhibitors are primarily type I kinase inhibitors that preferentially bind activated (versus inactive) kinase17. Kinase capture is highly reproducible and is a function of kinase affinity for different immobilized inhibitors as well as the kinase activation state. Activated kinases preferentially bind, inactive kinases do not. By coupling MIB capture with mass spectrometry (MIB/MS), the technique allows quantitative interrogation of hundreds of kinases in a single mass spectrometry run. This also interrogates kinases known by sequence but which have been understudied due to lack of reagents such as specific phospho-antibodies. We report here both in preclinical models and patients that BL and CL TNBC have different baseline kinome activation states and both respond differently to MEKi with subtype-specific tyrosine kinase reprogramming. To avoid treatment strategy that uses multiple kinase inhibitors in individual patients, we discovered a novel pharmacologic strategy to block the initial reprogramming response to MEKi involving inhibition of epigenetic processes.
2017-03-31 | GSE50550 | GEO
Project description:Enhancer Remodeling During Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacological Targeting of the P-TEFb Complex (Exome-seq)
| PRJNA344764 | ENA