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Project description:Id1 in mutant KRAS lung adenocarcinoma
| PRJNA427431 | ENA
Project description:The identification of novel therapeutic strategies to overcome the intrinsic or acquired resistance to trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a major challenge. This study analyzes the effects of trametinib in Id1, a key factor involved in the oncogenic KRAS pathway, and investigates the Id1 role in acquire resistance and synergy with immunotherapy in KRAS-driven LUAD. Restoring the antitumor immune response by blocking programmed-cell death protein 1 (PD-1) and programmed-cell death-ligand 1 (PD-L1) pathway represents a major breakthrough in non-small-cell lung cancer (NSCLC) treatment. Nevertheless, a high proportion of LUAD patients with KRAS alterations remain refractory to this therapy. Material and Methods: To explore whether MEK1/2 inhibition reduces Id1 expression, in vitro and in vivo experiments were conducted in KRAS-mutant NSCLC cells and murine models. RNAseq analysis was performed to elucidate the pathways involved in Id1 inhibition. Apoptosis and PD-L1 expression was measured by flow cytometry. Synergy of trametinib combined with anti-PD1 was investigated in KRAS-mutant LUAD mouse models. Results: Using preclinical syngeneic KRAS-mutant lung cancer mouse models, we demonstrate that trametinib synergizes with PD-1 blockade to reduce lung cancer progression and increase mice overall survival. This antitumor activity was linked to the degradation of Id1 via proteasome, and an enhanced INF-Y-mediated PD-L1 tumor cell expression in KRAS-mutant tumor cells. This effect required CD8+ T cells, boosted the intratumoral CD8+/Treg ratio, reducing the intratumoral Treg/CD4+ ratio. Conclusions: Our data may support the role of Id1 in the trametinib antitumoral effect, sustaining the mitogen-activated protein kinases (MAPK) signaling pathway involved in the trametinib acquired resistance cells and sensitizing KRAS-mutant lung tumors to PD-1 inhibitors, through PD-L1 overexpression.
2024-05-17 | GSE236258 | GEO
Project description:Mutant KRAS lung adenocarcinoma cells, H2009, were depleted of FOSL1 by a specific shRNA and its transcriptome was profiled
2017-06-12 | GSE76290 | GEO
Project description:Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.
2023-11-01 | GSE246481 | GEO
Project description:Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.
2023-11-01 | GSE246480 | GEO
Project description:KRAS mutations occur in approximately 25% of non-small cell lung cancer (NSCLC). They account for the therapy resistance to EGFR inhibitors and are suggested to be difficult to target by specific drugs. Therefore, new therapies for KRAS mutant NSCLC are urgently needed. The histone H3K4 and H3K9 di/mono-demethylase KDM1A is a key epigenetic writer, aberrantly upregulated in many cancer types, including NSCLC. In order to understand the functional role of KDM1A in the progression of lung adenocarcinoma, KDM1A expression profiles were analysed in tissue microarrays (TMAs) including 182 lung adenocarcinoma. KDM1A expression correlated with high grade and metastasized tumor. To investigate the impact of KDM1A in lung adenocarcinoma development, we used the KRAS mutated A549 cell line to establish a shRNA-mediated stable KDM1A knockdown cell clone. Unexpectedly, KDM1A knockdown had only a slight effect on retardation of cell growth. However, cell invasion and self-renewal capability was significantly decreased by KDM1A inhibition. KDM1A knockdown in A549 cell resulted in a dramatic change in the transcriptome profile as determined by RNA-Seq. Interestingly, genes involved in the KRAS signature and lung epithelial marker genes were significantly affected upon KDM1A knockdown. Ingenuity pathway analysis also suggested that the alternative integrin β3-KRAS signaling axis, which is involved in stem cell like properties, is abrogated upon KDM1A knockdown. Indeed, Integrin β3 and its non-canonical ligand galectin-3 were strongly downregulated and their downstream NF-κB activity was decreased upon KDM1A knockdown. Finally, correlation of KDM1A to the Integrin β3 level was validated in TMAs.
2017-03-13 | GSE86874 | GEO
Project description:Mechanisms underlying cancer stemness in Kras-mutant lung adenocarcinoma (KM-LUAD) are poorly understood. We previously found that mice with knockout of Gprc5a develop LUADs with somatic Kras mutations. We also previously derived Gprc5a-/- KM-LUAD cells (MDA-F471 cells) from a mouse exposed to the tobacco-specific carcinogen NNK. We also derived cancer stem cells (CSCs; grown and cultured as spheres in 3D cultures) from MDA-F471 cells. To better understand the biology of these CSCs, we compared the transcriptomes of MDA-F471 cells and their CSC counterparts by bulk RNA-sequencing.
2022-11-30 | GSE219124 | GEO
Project description:Based on the previous eVIP study (Cancer Cell, 2016), we profiled the transcriptomes of lung adenocarcinoma cell lines expressing oncogenic KRAS and TP53 to compare methods and investigate the effects of these oncogenes on the cells' whole transcriptomes.
2021-10-01 | GSE183670 | GEO
Project description:Proteomic studies to check the effect of MEK1/2 and KRAS G12C inhibitors in lung cancer cells
2023-08-22 | PXD024023 | Pride
Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
2015-02-05 | E-GEOD-52798 | biostudies-arrayexpress