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A Study of LY3499446 in Participants With Advanced Solid Tumors With KRAS G12C Mutation

ABSTRACT: The reason for this study is to see if the study drug LY3499446 is safe and effective in participants with solid tumors with KRAS G12C mutation.

DISEASE(S): Colorectal Cancer,Non-small Cell Lung Cancer,Advanced Solid Tumor,Colorectal Neoplasms,Carcinoma, Non-small-cell Lung

PROVIDER: 2322075 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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SHP2 Inhibition Abrogates Adaptive Resistance to KRAS-G12C-Inhibition and Remodels the Tumor Microenvironment of KRAS-Mutant Tumors

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.

2020-10-01 | GSE149815 | GEO

KRAS G12C inhibition combined with CD47 and immune checkpoint blockage overcomes intrinsic resistance to concomitant KRAS G12C and immune checkpoint inhibitor therapy

Project description:Although KRAS G12C inhibitors have altered the treatment strategy of patients with KRAS G12C mutant lung cancer, their efficacy is insufficient to eliminate tumors. Here, we identified that inhibition of mutant KRAS promotes escape from macrophage phagocytosis by upregulating the expression of ‘don’t eat me’ signal proteins, including CD47. CD47 was induced by the binding of FOXA1 to the super-enhancer of CD47. The addition of an anti-CD47 antibody restored macrophage phagocytosis and phenotype of macrophages.

2025-07-15 | GSE291687 | GEO

First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation

Project description:The purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of JNJ-74699157 in participants with advanced solid tumors harboring a kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation (Part 1: Dose escalation) and to determine the safety and preliminary antitumor activity of JNJ-74699157 at the RP2D regimen in participants with advanced solid tumors harboring a KRAS G12C mutation (Part 2: Dose expansion).

| 2309880 | ecrin-mdr-crc

Genome-Wide CRISPR Screen Identifies Multiple Synthetic Lethal Targets That Enhance KRAS (G12C) Inhibitor Efficacy [CRISPR]

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.

2023-09-11 | GSE240110 | GEO

Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor

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

Genome-Wide CRISPR Screen Identifies Multiple Synthetic Lethal Targets That Enhance KRAS (G12C) Inhibitor Efficacy [scRNA-seq]

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

Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)

Project description:The purpose of this study is to find out whether the study drug, LY3537982, is safe and effective in cancer patients who have a specific genetic mutation (KRAS G12C). Patients must have already received or were not able to tolerate the standard of care, except for specific groups who have not had cancer treatment. The study will last up to approximately 4 years.

| 2382898 | ecrin-mdr-crc

Genome-Wide CRISPR Screen Identifies Multiple Synthetic Lethal Targets That Enhance KRAS (G12C) Inhibitor Efficacy [RNA-seq-mm10]

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

Mapping the Interactome of KRAS and Its G12C/D/V Mutants by Integrating TurboID Proximity Labeling with Quantitative Proteomics

Project description:RAS is one of the most frequently mutated proto-oncogenes in human malignancies, with mutation sites and subtypes exhibiting tumor-type dependent distribution. Oncogenic RAS mutations will maintain continuously GTP-bound activation states that leading to dysregulation of downstream signaling, ultimately disrupting cellular homeostasis to induce malignant transformation of cells. In this study, we employed TurboID proximity-labeling technology integrated with quantitative proteomics LC-MS/MS to systematically characterize the proximal binding proteins of wild-type KRAS and three high-frequency oncogenic mutant subtypes G12C, G12D and G12V. Through comprehensive bioinformatic analysis of mutation-specific interaction networks and distinct metabolic pathways, we identified significant enrichment of mutant KRAS binding proteins in insulin signaling pathway, reactive oxygen species related pathways, glucose and lipid metabolism and so on. Metabolic reprogramming pathways in KRAS G12 mutations collectively fuel tumor proliferation and immune evasion. In addition, we also comparatively analyzed the proximal binding proteins similarity in three G12 mutants. Notably, we observed that the KRAS E3 ubiquitin ligase adaptor LZTR1 diminished binding with mutations, and the mTORC1 important regulatory protein LAMTOR1 was enhanced recruitment by mutations. This multi-dimensional profiling delineates a comprehensive mapping of KRAS WT and G12 mutant interactomes and unveils the metabolic reprogramming pathways associated with KRAS activating mutations. Our analysis result provides potential therapeutic targets for KRAS-driven tumorigenesis while establishing a mechanistic framework for developing KRAS mutation-specific therapeutic strategies.

2025-06-09 | PXD062101 | Pride

Molecular Determinants of Sotorasib Clinical Efficacy in KRAS G12C–Mutated Non–Small-Cell Lung Cancer

Project description:This study describes transcriptional subtypes of non-squamous non–small cell lung cancer (NSCLC). Baseline tissue samples (fresh/archival) were analyzed using a whole-transcriptome RNA assay (Tempus RS.v2; Tempus Labs, Inc., Chicago, IL, USA). Objectives included expression characterization of the KRAS G12C subject population with respect to genetic mutation (ATM, SMARCA4, KEAP1, STK11) and transcriptional signatures: KPCL (Skoulidis, Cancer Discov (2015) 5 (8): 860–877) & NRF2 activation (Singh, Clin Cancer Res (2021) 27 (3): 877–888).

2025-06-02 | GSE295032 | GEO

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