Scotto, L. | Search bioRxiv

bioRxiv2024

Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma-(PDAC) needs innovative approaches due to its 12% 5-year survival despite current therapies. We show marked sensitivity of pancreatic cancer cells to the combination of a novel eIF4A inhibitor, des-methyl pateamine A (DMPatA), and a histone deacetylase inhibitor, romidepsin, inducing epigenetic reprogramming as an innovative therapeutic strategy. Exploring the mechanistic activity of this combination showed that with a short duration of romidepsin at low doses, robust acetylation persisted up to 48h with the combination, while histone acetylation rapidly faded with monotherapy. This represents an unexpected mechanism of action against PDAC cells that triggers transcriptional overload, metabolic stress, and augmented DNA damage. Structurally different class I HDAC inhibitors exhibit the same hyperacetylation patterns when co-administered with DMPatA, suggesting a class effect. We show efficacy of this combination regimen against tumor growth in a MIA PaCa-2 xenograft model of PDAC with persistent hyperacetylation confirmed in tumor samples. STATEMENT OF SIGNIFICANCEPancreatic ductal adenocarcinoma, a significant clinical challenge, could benefit from the latent potential of epigenetic therapies like HDAC inhibitors-(HDIs), typically limited to hematological malignancies. Our study shows that a synergistic low dose combination of HDIs with an eIF4A-inhibitor in pancreatic cancer models results in marked pre-clinical efficacy, offering a promising new treatment strategy.

cancer biology↗

bioRxiv2020

CK1 Delta Is an mRNA Cap-Associated Protein That Drives Translation Initiation and Tumor Growth

Whether translation is differentially regulated across liquid and solid tumors remains poorly understood. Here we report the discovery that Casein Kinase 1 delta (CK1{delta}) plays a key role in regulating translation initiation in blood cancers, but interestingly, not in solid tumors. In lymphomas CK1{delta} is a key positive regulator of 4E-BP1 and p70S6K phosphorylation, assembly of eIF4F, and translation initiation. Furthermore, CK1{delta} is pulled down by m7GTP-agarose that mimics the mRNA m7G cap, consistent with the regulatory role of CK1{delta} in translation initiation. Targeting CK1{delta} using a small molecule inhibitor, namely SR-3029, potently kills lymphoma cell lines and primary lymphoma cells across histology subtypes. While SR-3029 shares with mTORC1 inhibitors the overlapping mechanism of repressing 4E-BP1 and p70S6K/RPS6 phosphorylation, the kinetics of repression is slow with SR-3029 and fast with mTORC1 inhibitors such as Torin-1. Remarkably, it is slower-acting SR-3029, but not fast-acting Torin-1, that kills lymphoma cells consistently across multiple histology subtypes. Proteomics and RNA sequencing studies show that SR-3029 represses the expression of many genes preferentially at the translation step, such as genes in the reactome translation initiation pathway. SR-3029 markedly represses the protein level of the C-MYC oncogene without decreasing its mRNA level. In contrast, Torin-1 fails to reduce the protein level of C-MYC in the same lymphoma cells. While SR-3029 also demonstrates potent activity in select solid tumors, its mechanism of action in the solid tumors is different. In breast cancer cells SR-3029 inhibits nuclear localization of {beta}-catenin but at the same concentrations does not inhibit 4E-BP1 and p70S6K phosphorylation or global protein synthesis. Likewise, SR-3029 does not inhibit nuclear localization of {beta}-catenin in lymphoma cells. Our results indicate that CK1{delta} is an mRNA cap-associated protein and an upstream kinase required for 4E-BP1 and p70S6K phosphorylation. CK1{delta} stimulates assembly of eIF4F and translation initiation, and is a critical driver for tumor growth in blood cancers across multiple histology types. CK1{delta} invokes the alternative mechanism of regulating {beta}-catenin in select solid tumors. Our results indicate that CK1{delta} inhibition is a promising therapeutic strategy in both liquid and solid tumors, and the distinct roles of CK1{delta} in these malignancies may serve as biomarkers to enable precision cancer treatment.

cancer biology↗