Selective NSD2 Inhibition Reveals an Epigenetic Vulnerability of KRAS-Driven Cancers [CUT&Run]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1142010 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30042500_1.fastq.gz | Fastqsanger.gz | |||
| SRR30042500_2.fastq.gz | Fastqsanger.gz | |||
| SRR30042501_1.fastq.gz | Fastqsanger.gz | |||
| SRR30042501_2.fastq.gz | Fastqsanger.gz | |||
| SRR30042502_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 240 |
Similar Datasets
Project description:NSD2, through generation of the epigenetic modification histone H3 di-methylated at lysine 36 (H3K36me2), is a candidate convergent downstream effector of oncogenic KRAS-signaling. However, whether NSD2 targeting represents a therapeutic vulnerability of KRAS-driven cancers is unknown. Here, we characterize a first-in-class, clinical grade small molecule catalyticNSD2inhibitor (NSD2i) series and find pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven pre-clinical cancer models. NSD2i inhibits NSD2 potently, with single digit nM IC50values, and shows high selectively for NSD2 versus NSD1, NSD3, and other similar enzymes. Structural analyses reveal the molecular basis of NSD2i specificity for NSD2, which includesS-adenosylmethionine (SAM)-competitive binding and catalytic disruption via a dual-channel obstruction mechanism. Proteo-epigenomic and single cell strategies in pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) samples support a model in which durable NSD2i exposure reverses H3K36me2-driven pathologic chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail KRAS-regulated and oncogenic-associated gene expression programs. Accordingly, NSD2i treatment inhibits PDAC and LUAD cell viability and patient-derived xenograft tumor growth. Further, NSD2 inhibition, which is well toleratedin vivo, is equally effective as KRAS inhibition (sotorasib) treatment in prolonging survival in advanced stage autochthonous KRASG12C-driven PDAC and LUAD mouse tumor models. Moreover, in these models, NSD2 inhibition and sotorasib co-treatment synergize to confer sustained survival with extensive tumor nodule regression and elimination.Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in KRAS-driven cancers and provides a mechanistic rationale for testing NSD2i-KRAS inhibition combination therapies in the clinic.
2025-04-12 | GSE273491 | GEO
Project description:NSD2, through generation of the epigenetic modification histone H3 di-methylated at lysine 36 (H3K36me2), is a candidate convergent downstream effector of oncogenic KRAS-signaling. However, whether NSD2 targeting represents a therapeutic vulnerability of KRAS-driven cancers is unknown. Here, we characterize a first-in-class, clinical grade small molecule catalyticNSD2inhibitor (NSD2i) series and find pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven pre-clinical cancer models. NSD2i inhibits NSD2 potently, with single digit nM IC50values, and shows high selectively for NSD2 versus NSD1, NSD3, and other similar enzymes. Structural analyses reveal the molecular basis of NSD2i specificity for NSD2, which includesS-adenosylmethionine (SAM)-competitive binding and catalytic disruption via a dual-channel obstruction mechanism. Proteo-epigenomic and single cell strategies in pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) samples support a model in which durable NSD2i exposure reverses H3K36me2-driven pathologic chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail KRAS-regulated and oncogenic-associated gene expression programs. Accordingly, NSD2i treatment inhibits PDAC and LUAD cell viability and patient-derived xenograft tumor growth. Further, NSD2 inhibition, which is well toleratedin vivo, is equally effective as KRAS inhibition (sotorasib) treatment in prolonging survival in advanced stage autochthonous KRASG12C-driven PDAC and LUAD mouse tumor models. Moreover, in these models, NSD2 inhibition and sotorasib co-treatment synergize to confer sustained survival with extensive tumor nodule regression and elimination.Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in KRAS-driven cancers and provides a mechanistic rationale for testing NSD2i-KRAS inhibition combination therapies in the clinic.
2025-04-12 | GSE273490 | GEO
Project description:NSD2, through generation of the epigenetic modification histone H3 di-methylated at lysine 36 (H3K36me2), is a candidate convergent downstream effector of oncogenic KRAS-signaling. However, whether NSD2 targeting represents a therapeutic vulnerability of KRAS-driven cancers is unknown. Here, we characterize a first-in-class, clinical grade small molecule catalytic NSD2 inhibitor (NSD2i) series and find pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven pre-clinical cancer models. NSD2i inhibits NSD2 potently, with single digit nM IC50 values, and shows high selectively for NSD2 versus NSD1, NSD3, and other similar enzymes. Structural analyses reveal the molecular basis of NSD2i specificity for NSD2, which includes S-adenosylmethionine (SAM)-competitive binding and catalytic disruption via a dual-channel obstruction mechanism. Proteo-epigenomic and single cell strategies in pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) samples support a model in which durable NSD2i exposure reverses H3K36me2-driven pathologic chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail KRAS-regulated and oncogenic-associated gene expression programs. Accordingly, NSD2i treatment inhibits PDAC and LUAD cell viability and patient-derived xenograft tumor growth. Further, NSD2 inhibition, which is well tolerated in vivo, is equally effective as KRAS inhibition (sotorasib) treatment in prolonging survival in advanced stage autochthonous KRASG12C-driven PDAC and LUAD mouse tumor models. Moreover, in these models, NSD2 inhibition and sotorasib co-treatment synergize to confer sustained survival with extensive tumor nodule regression and elimination. Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in KRAS-driven cancers and provides a mechanistic rationale for testing NSD2i-KRAS inhibition combination therapies in the clinic.
2025-04-16 | GSE273502 | GEO
Project description:NSD2, through generation of the epigenetic modification histone H3 di-methylated at lysine 36 (H3K36me2) is a candidate convergent downstream effector of oncogenic signaling. However, whether selective inhibition of NSD2 enzymatic activity at chromatin can serve as an effective cancer therapy is unknown. Here, we characterize a first-in-class, clinical grade small molecule catalytic NSD2 inhibitor (NSD2i) series and find that pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven pre-clinical cancer models. NSD2i potently inhibits NSD2 with single digit nM IC50 values and high selectivity over NSD1, NSD3, and other methyltransferases. Structural analyses reveal the molecular basis of NSD2i specificity for NSD2 includes S-adenosylmethionine (SAM)-competitive binding and catalytic disruption via a binary-channel obstruction mechanism. Proteo-epigenomic and single-cell strategies in pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) samples support a model in which sustained NSD2i exposure reverses H3K36me2-driven pathologic chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail KRAS-regulated and oncogenic-associated gene expression programs. Accordingly, NSD2i inhibits PDAC and LUAD cell viability and patient-derived xenograft tumor growth. Further, NSD2i, which is well-tolerated in vivo, prolongs survival in advanced-stage autochthonous KRASG12C-driven PDAC and LUAD mouse tumor models nearly as effectively as KRAS inhibition with sotorasib. Moreover, in these models, NSD2i synergizes with sotorasib to confer sustained survival with extensive tumor nodule regression and elimination. Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in KRAS-driven cancers and provides a mechanistic rationale for testing NSD2i-KRAS inhibitor combination therapies in the clinic.
2025-04-12 | GSE273492 | GEO
Project description:Selective NSD2 Inhibition Reveals an Epigenetic Vulnerability of KRAS-Driven Cancers [RNA-Seq]
| PRJNA1142008 | ENA
Project description:Selective NSD2 Inhibition Reveals an Epigenetic Vulnerability of KRAS-Driven Cancers [NicE-seq]
| PRJNA1142009 | ENA
Project description:Selective NSD2 Inhibition Reveals an Epigenetic Dependency of KRAS-Driven Cancers
| PRJNA1142022 | ENA
Project description:RNA-seq of kras and kras;NSD2 driven tumor biopsies and RNA-seq and Cut-and-run of kras;NSD2 derived cells suggests NSD2 amplifies Ras-output at chromatin and separately activates oncogenic-promoting gene expression programs.
2021-09-21 | GSE171217 | GEO
Project description:RNA-seq of kras and kras;NSD2 driven tumor biopsies and RNA-seq and Cut-and-run of kras;NSD2 derived cells suggests NSD2 amplifies Ras-output at chromatin and separately activates oncogenic-promoting gene expression programs.
2021-09-21 | GSE171216 | GEO
Project description:KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proven challenging and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success due to activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1 thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.
2020-08-20 | GSE128385 | GEO