Chronic responses to direct Ras-targetted therapies
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE206867 | GEO | 2022/06/27
REPOSITORIES: GEO
Similar Datasets
Project description:Activating mutants of RAS are commonly found in many human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we have developed a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. Affinity purification were performed on PATU8902 and H358 cell lines that contain KRAS(G12V) and KRAS(G12C), respectively, but not from growth factor stimulated HEK293T cells containing only wild-type RAS. The mass spectrometric data was acquired in data dependent mode to show the clear enrichment of KRAS in the 2 cell lines that carry the mutated RAS. In addition, a targeted analysis was performed for the peptide carrying the G12V mutation as well as the wild type KRAS peptide to further verify enrichment of only the KRAS mutant.
2020-12-07 | MSV000086569 | MassIVE
Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental H358 cells to those with acquired resistance to the KRAS G12C inhibitor, AMG510. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.
2025-10-08 | PXD055244 | Pride
Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental LUN156 patient-derived xenograft tumors to those with acquired resistance to the KRAS G12C inhibitors, Adagrasib (AR) and RM-4998 (RR). Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.
2025-10-08 | PXD055133 | Pride
Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental Lu65 cells to those with acquired resistance to the KRAS G12C inhibitor, Sotorasib. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.
2025-10-08 | PXD055167 | Pride
Project description:NCI-H358 is a KRAS G12C-mutant non-small lung cancer cell line known to be sensitive to KRAS G12C-inhibitor sotorasib. Here, we aimed to develop sotorasib resistance in H358 and interrogate the resulting sotorasib-resistant cell line (H358-R). The H358-R cell line was created by continuous culturing of the H358 cells in sotorasib (250 nM) until cells grew readily under sotorasib pressure (approximately 2 months). We then performed RNA-seq of the resulting sotorasib-resistant cell line (H358-R) with and without sotorasib pressure, compared to the parental sensitive cell line control (H358). KRAS gene expression level was found to be increased in the sotorasib-resistant line compared with the parental cells, likely representing a mechanism of resistance. The increased KRAS expression level in the resistant cell line was maintained under sotorasib pressure.
2025-09-24 | GSE277630 | GEO
Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental Lu65 cells to those with acquired resistance to RM-4998. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.
2025-10-08 | PXD055080 | Pride
Project description:We report RNAseq gene expression data following ARS-1620 treatment and shKRAS expressing cells (NCI-H358). We also compare gene expression changes following treatment with ARS-1620 or trametinib in NCI-H358, LU65 (KRAS-G12C+), and A549 (KRAS-G12S+) cells. Additionally we report a time course (4, 24, 48hr) of ARS-1620 and trametinib treated NCI-H358 cells.
2018-01-24 | GSE103021 | GEO
Project description:Chronic responses to direct Ras-targetted therapies
| PRJNA852535 | ENA
Project description:KRAS G12C inhibitors (G12Ci) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. KRAS plays a critical role in normal cell signaling; hence, G12Cis could influence the signaling pathways. We found that several novel pathways including Hippo pathways are upregulated upon MRTX849 treatment. Our results argue for testing KRAS G12C and TEAD inhibitor combinations in NSCLC patients.
2023-09-11 | GSE240118 | GEO
Project description:KRAS G12C inhibitors (G12Ci) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. KRAS plays a critical role in normal cell signaling; hence, G12Cis could influence the signaling pathways. We found that several novel pathways including Hippo pathways are upregulated upon MRTX849 treatment. Our results argue for testing KRAS G12C and TEAD inhibitor combinations in NSCLC patients.
2023-09-11 | GSE240113 | GEO