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HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq trametinib entinostat treatment]

ABSTRACT: HDAC3 is one of the main targets of Histone Deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. Here, we identified a critical role for HDAC3 in KRAS mutant lung cancer. Using genetic engineered mouse models (GEMM), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical new target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as KRAS/LKB1 mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the KRAS/LKB1 GEMM.

ORGANISM(S): Mus musculus

PROVIDER: GSE164757 | GEO | 2023/07/14

REPOSITORIES: GEO

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HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [ChIP-seq KL LJE1 cells]

Project description:HDAC3 is one of the main targets of Histone Deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. Here, we identified a critical role for HDAC3 in KRAS mutant lung cancer. Using genetic engineered mouse models (GEMM), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical new target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as KRAS/LKB1 mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the KRAS/LKB1 GEMM.

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Trametinib sensitizes KRAS-mutant lung adenocarcinoma tumors to PD-1/PD-L1 axis blockade via Id1 downregulation

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

Single cell RNA sequencing of tumor sections from GEMM harboring KrasG12D/+ or KrasG12D/+Lkb1fl/fl(KL) mutation.

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2022-07-16 | GSE180963 | GEO

Expression data from lung adenocarcinoma mouse tumors

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Differentially expressed genes in iKRAS tumor treated with Trametinib or Kras extinction

Project description:To identify the differentially expressed gene in ikras tumors treated with Trametinib or Kras extinction.

2021-06-07 | GSE176241 | GEO

Capicua-dependent transcriptional changes in human cancer cell lines treated with trametinib

Project description:We performed a genome-scale CRISPR screen in a KRAS-mutant pancreatic cancer cell line treated with the MEK inhibitor trametinib, and found that loss of the transcriptional repressor CIC confers resistance to MEK inhibition. We determined that CIC loss also confers resistance to MEK or BRAF inhibition in lung cancer, colorectal cancer, and melanoma cell lines with mutant RAS or BRAF. CIC is a transcriptional repressor that is phosphorylated and inhibited by the MAPK pathway. We hypothesized that inhibition of the MAPK pathway would lead to activation of CIC and repression of CIC target genes. Loss of CIC would therefore restore expression of these genes, conferring drug resistance. To identify the relevant CIC target genes that mediate trametinib resistace, we generated 4 Cas9-expressing cell lines from different lineages and with different RAS or RAF mutations, and generated control (gGFP) or CIC-knockout (gCIC) cell lines. We treated cells with DMSO or trametinib for 24 hours, and performed NRA-seq. We found that trametinib treatment reduces expression of at least one member of the PEA3 family of ETS transcription factors (ETV1, ETV4, and ETV5) in all cell lines assessed, and that loss of CIC results in maintained expression of these genes despite MEK inhibition. We further validated that ETV1, 4, and 5 expression was necessary for resistance mediated by CIC loss; and that ETV1, 4, or 5 expression was sufficient to confer trametinib resistance.

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