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Targeting the calcium-activated K+ channel KCa3.1 in pancreatic ductal adenocarcinoma

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, distinguished by its dense desmoplastic microenvironment and the scarcity of therapeutic options. Recent studies have identified the calcium-activated potassium channel KCa3.1 as a potential therapeutic target in oncology. There is a correlation between increased KCa3.1 expression and poor overall survival of PDAC patients. Therefore, we investigated the therapeutic potential of KCa3.1 targeting in PDAC using TRAM-34 and maurotoxin alone or in combination with gemcitabine. We utilized the KPfC (Kraswt/LSL–G12D Tp53fl/+ Pdx1-Cre) mouse model to evaluate the in vivo therapeutic efficacy of KCa3.1 inhibition. We developed a three-dimensional mixed spheroid model co-culturing pancreatic cancer cells and pancreatic stellate cells (PSCs) to mimic the tumor microenvironment. To gain mechanistic insights, we performed RNA sequencing on mixed spheroids containing KCa3.1 CRISPR knockout pancreatic cancer cells and explored the functional impact of KCa3.1 targeting in the spheroid model. In vivo, KCa3.1 inhibition led to a decrease in tumor growth without inducing excessive fibrosis. KCa3.1 inhibition was associated with increased cell death and diminished epithelial-mesenchymal transition (EMT). In vitro inhibition of the plasma membrane KCa3.1 channel by maurotoxin resulted in decreased invasive potential and increased cell death. These effects can mechanistically account for the therapeutic benefits of targeting KCa3.1 channels in PDAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279207 | GEO | 2026/08/31

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

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Targeting the calcium-activated K+ channel KCa3.1 in pancreatic ductal adenocarcinoma

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