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STAT3 inhibitors synergize with KRAS G12C inhibitors in NSCLC by restricting adaptive resistance of STAT3 signaling and augmenting NK cell cytotoxicity

ABSTRACT: STAT3 inhibitors synergize with KRAS G12C inhibitors in NSCLC by restricting adaptive resistance of STAT3 signaling and augmenting NK cell cytotoxicity

PROVIDER: PRJNA1139220 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29935632_1.fastq.gz	Fastqsanger.gz
	SRR29935632_2.fastq.gz	Fastqsanger.gz
	SRR29935633_1.fastq.gz	Fastqsanger.gz
	SRR29935633_2.fastq.gz	Fastqsanger.gz
	SRR29935634_1.fastq.gz	Fastqsanger.gz

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STAT3 inhibitors synergize with KRAS G12C inhibitors in NSCLC by restricting adaptive resistance of STAT3 signaling and augmenting NK cell cytotoxicity

Project description:KRASG12C inhibitors have demonstrated clinical efficacy in KRASG12C-mutant non-small cell lung cancer (NSCLC), yet adaptive resistance limits their sustained therapeutic benefit. Through high-throughput screening of a pharmacological library, we identified a potent synergistic interaction between the KRASG12C inhibitor sotorasib and the signal transducer and activator of transcription 3 (STAT3) inhibitor napabucasin in KRASG12C-mutant NSCLC models. This combination exhibited superior anti-neoplastic activity compared to monotherapy in vitro and across diverse in vivo models. Mechanistically, KRASG12C inhibitor induced compensatory STAT3 activation, leading to adaptive resistance to sotorasib, which was abrogated by napabucasin. Notably, we elucidated a novel function of STAT3 in regulating HLA-B expression, an inhibitory ligand for natural killer (NK) cells, upon KRASG12C inhibition. The combination therapy enhanced NK cell-mediated cytotoxicity by disrupting the direct binding of phosphorylated STAT3 to the HLA-B promoter to downregulate its expression on neoplastic cells. Our findings unveiled an unexpected immunomodulatory mechanism underlying the synergism between KRAS and STAT3 inhibition, highlighting the potential of concurrently targeting oncogenic signaling cascades and the tumor microenvironment. This study provides a compelling rationale for the clinical evaluation of combined KRASG12C and STAT3 interruption in KRASG12C-mutant NSCLC patients, potentially offering a novel therapeutic strategy to overcome resistance and improve clinical outcomes.

2025-05-07 | GSE272914 | 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

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

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

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

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

Resistance to Spindle inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence

Project description:While mitotic spindle inhibitors specifically kill proliferating tumor cells without the toxicities of microtubule poisons, resistance has limited their clinical utility. Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of STAT3. Furthermore, these senescent cells expand the repertoire of resistant cells by secreting an array of factors, including TGFb, which induce proliferating cells to exit mitosis and become quiescent—a state that is also insensitive to spindle inhibitors. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. We have incorporated our results into a model that explains how STAT3 and therapy induced senescence combine to drive resistance, which can provide insight into how to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma.

2024-10-28 | GSE267458 | GEO

Transcription profiling of mouse embryonic stem cells to identify genes regulated by STAT3 and NANOG, known differentiation inhibitors

Project description:This experiment is part of the FunGenES project (FunGenES - Functional Genomics in Embryonic Stem Cells partially funded by the 6th Framework Programme of the European Union, http://www.fungenes.org). The experiment was conducted at the Inst. National de la SantÃ© et de la Recherche MÃ©dicale - INS (INSERM U371, Bron, France) The goal of the experiment is to identify genes regulated by STAT3 and NANOG, which are known inhibitors of mouse ES cell differentiation.(I) E14-Cre-CTL cells deprived of LIF for 24 hours (n = 5); (II) E14-Cre-Tax cells as in (I) and restimulated with 100 nM tamoxifen for 2 hours (n = 5); (III) E14-STATA3-CTL cells deprived of LIF and 4âOHT for 24 hours (n = 4); (IV) E14-STAT3-LIF cells treated as in (III) and re-stimulated with 10,000 U/ml LIF for 1 hour to reactivate endogenous STAT3 (n = 5); (V) E14-STAT3-Tax cells as in (III) and restimulated with 100 nM 4âOHT for 2 hours to activate STAT3-ERT2 (n = 6);

2009-03-01 | E-TABM-562 | biostudies-arrayexpress

CDKN1B (p27kip1) enhances drug tolerant persister CTCs by restricting polyploidy following mitotic inhibitors.

Project description:CDKN1B (p27kip1) enhances drug tolerant persister CTCs by restricting polyploidy following mitotic inhibitors.

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Exploring the roles of Notch inhibitors and STAT3 inhibitors in the regulation of liver cancer proliferation

Project description:Exploring the roles of Notch inhibitors and STAT3 inhibitors in the regulation of liver cancer proliferation

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