Pan KRAS inhibitor selectively inactivates oncogenic signaling and tumor growth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA947663 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23943103_1.fastq.gz | Fastqsanger.gz | |||
| SRR23943103_2.fastq.gz | Fastqsanger.gz | |||
| SRR23943104_1.fastq.gz | Fastqsanger.gz | |||
| SRR23943104_2.fastq.gz | Fastqsanger.gz | |||
| SRR23943105_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 176 |
Similar Datasets
Project description:To investigate the effect of KRASi treatment on transcriptional output, we sequenced RNAs from 22 cell lines with different KRAS genotypes. We then performed gene expression profiling analysis using data obtained from RNA-seq comparing untreated and 2hr treated samples.
2023-06-02 | GSE228010 | GEO
Project description:KRAS is the most frequently mutated oncogene in human cancers, but to date, only KRASG12C inhibitors have been FDA-approved. Small-molecule inhibitors that target other more prevalent KRAS mutations are in urgent clinical need. Here, we report a highly potent pan-KRAS inhibitor, MCB-294, that selectively targets KRAS, but not HRAS or NRAS. Molecular profiling studies show that MCB-294 binds to and inhibits several KRAS mutants, including G12D, G12C, G12V, thereby disabling KRAS oncogenic signaling. MCB-294 is well tolerated in mice and exhibits remarkable therapeutic efficacy against the growth of a comprehensive range of KRAS-driven cancer cell lines, patient-derived organoids, and tumor xenografts and prolongs mouse survival. By employing an MCB-294 derivative as the KRAS binder, we further identify a VHL-based pan-KRAS degrader, MCB-36, that efficiently degrades KRAS in vitro and in vivo through the ubiquitin-proteasome system. Importantly, MCB-294 and MCB-36 not only effectively kill KRASG12C inhibitor-resistant cells, but also reshape the tumor microenvironment by boosting T cell-mediated anti-tumor immunity. Taken together, our findings demonstrate a successful and feasible strategy for targeting pan-KRAS to impair multifaceted features of KRAS-driven cancers.
2024-08-03 | GSE273300 | GEO
Project description:KRAS is the most frequently mutated oncogene in human cancers, but to date, only KRASG12C inhibitors have been FDA-approved. Small-molecule inhibitors that target other more prevalent KRAS mutations are in urgent clinical need. Here, we report a highly potent pan-KRAS inhibitor, MCB-294, that selectively targets KRAS, but not HRAS or NRAS. Molecular profiling studies show that MCB-294 binds to and inhibits several KRAS mutants, including G12D, G12C, G12V, thereby disabling KRAS oncogenic signaling. MCB-294 is well tolerated in mice and exhibits remarkable therapeutic efficacy against the growth of a comprehensive range of KRAS-driven cancer cell lines, patient-derived organoids, and tumor xenografts and prolongs mouse survival. By employing an MCB-294 derivative as the KRAS binder, we further identify a VHL-based pan-KRAS degrader, MCB-36, that efficiently degrades KRAS in vitro and in vivo through the ubiquitin-proteasome system. Importantly, MCB-294 and MCB-36 not only effectively kill KRASG12C inhibitor-resistant cells, but also reshape the tumor microenvironment by boosting T cell-mediated anti-tumor immunity. Taken together, our findings demonstrate a successful and feasible strategy for targeting pan-KRAS to impair multifaceted features of KRAS-driven cancers.
2024-08-03 | GSE273301 | GEO
Project description:KRAS is the most frequently mutated oncogene in human cancers, but to date, only KRASG12C inhibitors have been FDA-approved. Small-molecule inhibitors that target other more prevalent KRAS mutations are in urgent clinical need. Here, we report a highly potent pan-KRAS inhibitor, MCB-294, that selectively targets KRAS, but not HRAS or NRAS. Molecular profiling studies show that MCB-294 binds to and inhibits several KRAS mutants, including G12D, G12C, G12V, thereby disabling KRAS oncogenic signaling. MCB-294 is well tolerated in mice and exhibits remarkable therapeutic efficacy against the growth of a comprehensive range of KRAS-driven cancer cell lines, patient-derived organoids, and tumor xenografts and prolongs mouse survival. By employing an MCB-294 derivative as the KRAS binder, we further identify a VHL-based pan-KRAS degrader, MCB-36, that efficiently degrades KRAS in vitro and in vivo through the ubiquitin-proteasome system. Importantly, MCB-294 and MCB-36 not only effectively kill KRASG12C inhibitor-resistant cells, but also reshape the tumor microenvironment by boosting T cell-mediated anti-tumor immunity. Taken together, our findings demonstrate a successful and feasible strategy for targeting pan-KRAS to impair multifaceted features of KRAS-driven cancers.
2024-07-30 | GSE273116 | GEO
Project description:The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. This SuperSeries is composed of the following subset Series:; GSE17643: Profiling of immortalized human lung epithelial cells following oncogenic KRAS expression and TBK1 suppression; GSE17671: Profiling of immortalized human lung epithelial cells following infection with oncogenic KRAS (G12V) Experiment Overall Design: Refer to individual Series
2009-10-31 | E-GEOD-17672 | biostudies-arrayexpress
Project description:Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue1. However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand2. Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders. This is the proteomics analysis of ACBI3 and compoun 8, its negative control.
2024-10-01 | PXD050650 | Pride
Project description:The purpose of the dataset is to analyze expression of genes induced by KRAS; The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. Experiment Overall Design: Profiling of KRAS activation (mutant), KRAS WT and control in AALE cells (Lundberg et al., Oncogene 2002;21:4577)
2009-10-31 | E-GEOD-17671 | biostudies-arrayexpress
Project description:The purpose of the dataset is to analyze expression of genes induced by KRAS and regulated by TBK1; The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. Experiment Overall Design: Knock out of TBK1 in the contect of KRAS activation (mutant) and control (WT)
2009-11-15 | E-GEOD-17643 | biostudies-arrayexpress
Project description:The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. This SuperSeries is composed of the SubSeries listed below.
2009-10-21 | GSE17672 | GEO
Project description:Oncogenic mutations in tumor cells regulate signaling both within tumor cells and heterotypic stromal cells. However, whether oncogenes regulate tumor cell signaling via stromal cells is poorly understood. Here we show that oncogenic KRAS (KRAS-G12D) uniquely regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with phosphoproteomic multiplexing we conducted a multivariate analysis of heterocellular KRAS-G12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. By engaging heterotypic fibroblasts, KRAS-G12D drives unique reciprocal signaling in tumor cells to employ additional kinases and double the number of regulated signaling nodes from cell-autonomous KRAS-G12D. Heterocellular signaling produces a distinct tumor cell phosphoproteome, total proteome, and increase mitochondria capacity via an IGF1R/AXL-AKT axis. Reciprocal KRAS-G12D phenotypes require a heterocellular context and are unreachable by cell-autonomous KRAS-G12D alone. These results demonstrate oncogene signaling should be viewed as a heterocellular process and our existing homocellular perspective underrepresents the extent of oncogene signaling in cancer.
2016-04-19 | PXD003223 | Pride