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PRMT1 promotes pancreatic cancer development and resistance to chemotherapy

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of, and potential as a therapeutic target for, PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that the PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223152 | GEO | 2024/03/09

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a nearly uniformly lethal malignancy, with most patients facing an adverse clinical outcome. Given the pivotal role of aberrant Notch signaling in the initiation and progression of PDAC, we investigated the effect of MRK-003, a potent and selective γ-secretase inhibitor, in preclinical PDAC models. We used a panel of human PDAC cell lines, as well as patient-derived PDAC xenografts, to determine whether pharmacological targeting of the Notch pathway could inhibit pancreatic tumor growth and potentiate gemcitabine sensitivity. In vitro, MRK-003 treatment downregulated the canonical Notch target gene Hes-1, significantly inhibited anchorage independent growth, and reduced the subset of CD44+CD24+ and aldehyde dehydrogenase (ALDH)+ cells that have been attributed with tumor initiating capacity. Ex vivo pretreatment of PDAC cells with MRK-003 in culture significantly inhibited the subsequent engraftment in immunocompromised mice. In vivo, MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) patient-derived PDAC xenografts. Moreover, a combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared to gemcitabine alone in 4 of 9 (44%) PDAC xenografts. Baseline gene expression analysis of the treated xenografts indicated that upregulation of nuclear factor kappa B (NFκB) pathway components was associated with the sensitivity to single MRK-003, while upregulation in B-cell receptor (BCR) signaling and nuclear factor erythroid-derived 2-like 2 (NRF2) pathway correlated with response to the combination of MRK-003 with gemcitabine. The preclinical findings presented here provide further rationale for small molecule inhibition of Notch signaling as a therapeutic strategy in PDAC. Pancreatic ductal adenocarcinoma xenografts were grown in Athymic Nude-Foxn1nu mice. RNA was extracted and profiled in Affymetrix platform to identify genes correlating with sensitivity to MRK-003

Project description:Chemoresistance to gemcitabine limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an antibody drug conjugate (ADC) -like agent, EGFR/HER2 dual-targeting ligand-based lidamycin (DTLL), and studied the effect of DTLL combined with gemcitabine and the potential role of SMAD4 in the chemoresistance of PDAC. On the basis of SMAD4 profiles in in vitro and in vivo models, we investigated the antitumor effects of DTLL, gemcitabine and their combination, followed with mechanistic characterization. The results suggested that DTLL combination treatment with gemcitabine significantly repressed tumors with remarkably enhanced efficacy as compared to gemcitabine or DTLL alone given in either SMAD4-deficient/gemcitabine-resistant or SMAD4-sufficient/gemcitabine-sensitive cell line derived xenograft (CDX) and patient derived xenograft (PDX) tumors, respectively. Functional studies indicated that SMAD4 genetic status is responsible for SMAD4 protein level which determines different cellular susceptibility of PDAC. R100T mutation contributes to loss of SMAD4 protein and function with rapid protein degradation, leading to resistance to gemcitabine in PDAC cells. Moreover, DTLL significantly altered the protein half-life time and level of mutant and wild-type SMAD4 by inhibiting protein degradation at different velocities and distinctly changing the interaction of SMAD4 with TRIM33. Mechanism studies implied that DTLL combinational treatment might not only prevent from neoplastic proliferation via blockage of ATK/mTOR signaling and anti-apoptotic proteins (Bcl-2 and MCL1) mediated by impaired NF-B function in SMAD4-sufficient/gemcitabine-sensitive PDAC cells, but also restore the bioactivity of SMAD4 as a tumor suppressor to trigger its downstream NF-B-regulated signaling of cell apoptosis in SMAD4-deficient/gemcitabine-resistant tumors. In conclusion, SMAD4 is the key central mediator of not only the occurrence and development but also susceptibility in PDAC. DTLL sensitized gemcitabine efficacy via distinct action mechanisms based on SMAD4 profiles in SMAD4-sufficient/gemcitabine-sensitive and SMAD4-deficient/-resistant PDAC, respectively. Our findings provide insight into a rational SMAD4-directed precision treatment strategy and reveal a promising DTLL combination therapy to overcome chemoresistance in gemcitabine-resistant PDAC.

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PRMT1 promotes pancreatic cancer development and resistance to chemotherapy

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