ATAC-seq of NCI-H358 cells treated with KRAS G12C inhibitor sotorasib
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PROVIDER: PRJNA1106537 | ENA |
REPOSITORIES: ENA
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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:ATAC-seq of sotorasib-resistant NCI-H358 cells treated with sotorasib
2025-07-15 | GSE266309 | GEO
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:Patients with non-small cell lung cancer (NSCLC) who initially respond to Sotorasib, a drug targeting the KRAS G12C mutation, eventually develop acquired resistance. However, the mechanisms driving this acquired resistance remain largely unclear. This study explored the role of AURKA in mediating resistance to Sotorasib in NSCLC. The expression levels of AURKA mRNA and protein in NSCLC cell lines (H358 and Calu-1) were assessed using qPCR and Western blot. To further elucidate the role of AURKA in the biological alterations of Sotorasib-resistant cells and its association with the PI3K/AKT signaling pathway, a comprehensive set of assays were conducted, including MTS, colony formation, Transwell migration, luciferase reporter assays, fluorescent in situ hybridization (FISH), molecular docking analyses, and immunoprecipitation. The key findings include: (1) Long-term Sotorasib treatment led to upregulation of AURKA; (2) Overexpression of AURKA induced Sotorasib resistance, suppressed apoptosis and promoted migratory potential in Calu-1 and H358 cells, while AURKA knockdown increased the sensitivity, enhanced apoptosis and inhibited migratory capacity of H358-SR and Calu-1-SR cells to Sotorasib; (3) Immunoprecipitation and luciferase reporter assays demonstrated a physical interaction between AURKA and PHB2, establishing a positive feedback loop that sustained malignant behaviors, potentially explaining how Sotorasib-resistant cells survived despite KRAS pathway inhibition; (4) AURKA stabilizes PHB2, activating the PI3K/AKT pathway and allowing cancer cells to bypass the KRAS blockade, thus restoring malignant behavior. (5) The combination of AURKA inhibitor and Sotorasib alleviates the acquired drug resistance in vitro and in vivo. These data suggest that resistance to Sotorasib in NSCLC is associated with a positive feedback loop involving AURKA, PHB2, and PI3K/AKT signaling. AURKA may serve as a biomarker for predicting the therapeutic efficacy of Sotorasib in KRAS G12C-targeted therapies and as a potential therapeutic target to overcome Sotorasib resistance in NSCLC.
2026-01-17 | GSE316749 | GEO
Project description:To characterize sotorasib resistance in lung adenocarcinomas (LUAD), we generated genetically engineered mice (Kras-G12C, Trp53-KO) and compared the transcriptional profiles of untreated and sotorasib-resistant tumors
2023-03-05 | GSE204752 | GEO
Project description:Treatment of NSCLC KRAS G12C mutant tumors with targeted KRAS inhibitors, such as sotorasib and adagrasib, is invariably associated with the emergence of acquired resistance. The mechanisms responsible for resistance to these agents have largely remained unclear. We report that patients with NSCLC KRAS G12C tumors expressing increased levels of the MUC1 gene exhibit decreases in overall survival in response to sotorasib and adagrasib. In investigating the basis for this finding, we found that exposure of NSCLC KRAS G12C mutant cells to these agents induces expression of the oncogenic MUC1-C/M1C protein. We show that M1C induction is STAT1 dependent and that targeting M1C increases sensitivity to sotorasib. Studies of sotorasib-resistant cells further reveal upregulation of M1C chromatin levels in association with activation of the epithelial-mesenchymal transition (EMT). Mechanistically, M1C drives NF-kB p65-mediated induction of the ZEB1 EMT-TF. Furthermore, targeting M1C NF-kB ZEB1 signaling suppresses EMT and sotorasib resistance. Having identified this M1C dependence, we demonstrate that targeting M1C with an antibody-drug conjugate (ADC) is effective against sotorasib-resistant cells growing in vitro and as tumor xenografts. These findings identify M1C as a major effector of sotorasib resistance and as a target for ADC treatment of patients with refractory NSCLC KRAS G12C mutant tumors.
2026-07-15 | GSE315052 | GEO
Project description:A human kinome CRISPR knockout screen in H358 parental and sotorasib-R H358 cells using Addgene pooled libraries (#75314).
2025-10-07 | GSE275314 | GEO
Project description:The efficacy of KRAS-G12C inhibitors in lung cancer is limited by the rapid onset of acquired resistance. While divergent mechanisms of resistance across patients and preclinical models have complicated efforts to identify therapeutic strategies for sotorasib-resistant cancers, we found that sotorasib-resistant H358 and LU65 cell lines, which have distinct mechanisms of resistance and drug sensitivity profiles, both exhibited increased vulnerability to treatment with SR-4835, an inhibitor of the transcriptional kinases CDK12 and CDK13. To identify CDK12/13-dependent genes linked to the increased sensitivity we observed in sotorasib-resistant over parental cells, we treated parental and sotorasib-resistant H358 and LU65 cells with SR-4835 and performed RNA sequencing.
2025-10-07 | GSE288707 | GEO
Project description:Treatment of NSCLC KRAS G12C mutant tumors with targeted KRAS inhibitors, such as sotorasib and adagrasib, is invariably associated with the emergence of acquired resistance. The mechanisms responsible for resistance to these agents have largely remained unclear. We report that patients with NSCLC KRAS G12C tumors expressing increased levels of the MUC1 gene exhibit decreases in overall survival in response to sotorasib and adagrasib. In investigating the basis for this finding, we found that exposure of NSCLC KRAS G12C mutant cells to these agents induces expression of the oncogenic MUC1-C/M1C protein. Studies of RAS(ON)-resistant (RMC-R) cells further reveal upregulation of M1C chromatin levels in association with activation of the epithelial-mesenchymal transition (EMT). Mechanistically, M1C drives NF-kB p65-mediated induction of the ZEB1 EMT-TF. Furthermore, targeting M1C NF-kB ZEB1 signaling suppresses EMT and sotorasib resistance. Having identified this M1C dependence, we demonstrate that targeting M1C with an antibody-drug conjugate (ADC) is effective against sotorasib-resistant cells growing in vitro and as tumor xenografts. These findings identify M1C as a major effector of sotorasib resistance and as a target for ADC treatment of patients with refractory NSCLC KRAS G12C mutant tumors.
2026-07-15 | GSE324125 | GEO
Project description:Sotorasib is a selective inhibitor of KRAS G12C. In this study, miRNA expression changes in response to sotorasib exposure were analyzed by sequencing in MIA PaCa-2 pancreatic cancer cells harboring a KRAS G12C mutation.
2026-07-09 | GSE335375 | GEO