Molecular Determinants of Sotorasib Clinical Efficacy in KRAS G12C–Mutated Non–Small-Cell Lung Cancer
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ABSTRACT:
PROVIDER: PRJNA1252675 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33211100_1.fastq.gz | Fastqsanger.gz | |||
| SRR33211100_2.fastq.gz | Fastqsanger.gz | |||
| SRR33211001_1.fastq.gz | Fastqsanger.gz | |||
| SRR33211001_2.fastq.gz | Fastqsanger.gz |
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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
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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: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 (SR) 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.
2026-09-23 | GSE324028 | 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 (SR) 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.
2026-09-23 | GSE315054 | GEO
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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: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 H23 lung cancer cells harboring a KRAS G12C mutation.
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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
Project description:Invasive mucinous adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with a poor prognosis. Compared to non-small cell lung cancer (NSCLCs), IMA more frequently harbors KRAS mutations in the order KRAS p.G12V, p.G12D, and p.G12C. This report describes a patient with KRAS p.G12C-mutant IMA treated with sotorasib. To date, no studies have investigated the therapeutic efficacy or resistance mechanisms of sotorasib in IMA. The patient was treated with carboplatin and pemetrexed, followed by sotorasib upon disease progression. While the primary lung lesions responded well, metastatic thoracic lymph node lesions continued to increase. A pathological autopsy was performed with the family’s consent to investigate potential resistance mechanisms. RNA sequencing and additional analyses revealed increased VEGF-A expression in metastatic lymph node lesions, suggesting a role in sotorasib resistance. These findings provide insights into the molecular mechanisms underlying treatment resistance in KRAS p.G12C-mutant IMA.
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