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RNA-seq analysis of combination effect of H3B-6527 and Lenvatinib treatment in the Hep3B in vivo model

ABSTRACT: To investigate the underlying mechanism of the enhanced combination effect of H3B-6527 and Lenvatinib, we conducted RNA-seq analysis of Hep3B cell line xenograft tumors following treatment of tumor bearing mice with one dose of H3B-6527 or Lenvatinib as single agents or in combination. Principal component analysis and hierarchical clustering of differentially expressed genes (differentially expressed genes with adjusted p value < 0.05) showed two largely separated groups in which vehicle and Lenvatinib samples are close to each other whereas the H3B-6527 and the combination samples show similar pattern (Fig. 4A and 4B), suggesting Lenvatinib at 10mg/kg does not drastically alter transcriptional profiles of tumor cells. We then performed pathway enrichment analysis of differentially expressed genes, which showed bile acid metabolism as the top upregulated pathway in H3B-6527 single-agent group, a well-known selective effect to the FGFR4 signaling pathway (Fig. 4C). E2F targets and MYC targets scored as the top downregulated pathways; an effect that is common among many receptor tyrosine kinases including FGFR4. Combination of H3B-6527 and Lenvatinib showed significant upregulation of hypoxia and glycolysis pathways, consistent with anti-angiogenic effect resulting in lack of oxygen and nutrients in tumor microenvironment (Fig. 4C). Moreover, the combination groups showed stronger effects on E2F targets as compared with the single agent groups, and explains the increased antitumor activity observed in efficacy experiments (Fig. 4D). In summary, the RNAseq analysis provided direct mechanistic evidence for the combined anti-angiogenic and anti-tumorigenic effects resulting in enhanced efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE198845 | GEO | 2022/07/13

REPOSITORIES: GEO

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Project description:We performed single-cell RNA sequencing of a lymphoma (OCI-Ly18) subcutaneous tumor harvested from NSG mice two weeks after infusion with CART19 plus DMSO or CART19 plus Venetoclax (Suppl. Fig. 3A). Lymphoma cells with shared gene expression profiles were clustered using uniform manifold and approximation (UMAP) analysis. We identified six clusters characterized by different cell-cycle phases (Suppl. Fig. 3B), including one G1-dominant cluster, two S clusters, one G1/G2 cluster, one G2/M cluster, and an M cluster with high Ki67 expression. First, we observed a substantially lower proportion of cells assigned to G1-dom in the CART19/venetoclax-treated condition (8.4%) than in the CART19-treated condition (24%). These indicated a prevalent depletion of the G1-dom cluster by the addition of venetoclax (Suppl. Fig. 4C). In accordance with recent reports that venetoclax can induce cell cycle arrest and death in tumor cells in G1 39, these results suggest that venetoclax treatment also enhances CART’s anti-tumor efficacy by hindering the progression of cell cycle. Interestingly, the “G1-dominant (G1-dom)” and the additional “MKI67hi” cluster (high proliferative cells) showed significant enrichment of genes corresponding to interferon-gamma responsiveness, suggesting that the cells of these two clusters might have been interacting with CART cells (Suppl. Fig. 4D). Of note, by performing GO enrichment analysis with differentially expressed genes (DEGs) between CART19 and CART19/venetoclax combination in the MKI67hi cluster that represent a rapidly proliferating tumor subpopulation, we identified several pathways, including enrichment of the negative regulation of the G2/M phase transition in the CART19/venetoclax-treatment condition in the MKI67hi cluster (Suppl. Fig. 4E and 4F). Taken together, these data implicate that venetoclax treatment enhances CART-mediated tumor killing by promoting tumor apoptosis and inhibiting the cell cycle in cancer cells while also enhancing the interferon responses in neoplastic B-cells when engaging CART cells.

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RNA-seq analysis of combination effect of H3B-6527 and Lenvatinib treatment in the Hep3B in vivo model

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