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.
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.
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
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.
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.
Project description:We measured gene expression using RNA-sequencing for two cell lines (H-23 and H-358) parental and their sotorasib-resistant equivalent without treatment or treated with with G12C KRAS inhibitor sotorasib (AMG510)