Project description:Single H358 cells analyzed using SCOPE2 on a TIMSTOF Flex mass spectrometer. Bruker .d folders, MGFs, Proteome Discoverer 2.5 and MaxQuant 1.6.17 results are uploaded.
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:Bruker .d files in support of a multiomics analysis of the KRASG12D inhibitor MRTX1133. Files are broken into multiple repositories because uploading 3,000 single cell proteomes plus the bulk proteomics and the metabolomics and the metabolism stuff is really painful. This is the multiplexed (SCOPE2 on a TIMSTOF Flex) .d files for approximately 2,000 single human cells. Metadata will be provided in Orsburn, 2023
Project description:We report that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells (51T-2D cells) harboring KRAS-G12C mutations. This synergy was especially pronounced following drug washout, indicating a durable cellular response. Mechanistically, the combinations induced sustained cell cycle arrest.
Project description:KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime goal. Recently, inhibitors (G12C-Is) that bind KRAS-G12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRAS-G12C activation and inhibitor engagement, we found that SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRAS-G12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models. The combination of SHP2-I and G12C-I evoked favorable changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using an inhibitor-resistant SHP2 mutant showed that SHP2 inhibition in PDAC cells is required for tumor regression and remodeling of the immune microenvironment, but SHP2-Is also had direct effects on angiogenesis. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies. G12C-Is show significant, but limited, efficacy as single agents, in part because of “adaptive resistance”. We find that combining G12C-Is with SHP2-Is abrogates adaptive resistance and results in favorable changes in the immune microenvironment that potentiate PD-1 blockade in KRAS-mutant malignancies. SHP2-Is also can have direct, context-dependent, effects on tumor vasculature.
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.
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.
Project description:Bruker .d files in support of a multiomics analysis of the KRASG12D inhibitor MRTX1133. Files are broken into multiple repositories because uploading 3,000 single cell proteomes plus the bulk proteomics and the metabolomics and the metabolism stuff is really painful. This is the multiplexed (SCOPE2 on a TIMSTOF Flex) .d files for approximately 2,000 single human cells. Metadata will be provided in Orsburn, 2023
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 has been reported to create resistance. We found several novel pathways, including Hippo pathways, are enriched from significant dropouts upon MRTX849 treatment. Our results argue for testing KRAS G12C and TEAD inhibitor combinations in NSCLC patients.