Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth.

Autor: Khan HY; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Mpilla GB; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Sexton R; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Viswanadha S; Rhizen Pharmaceuticals SA, 2300 La Chaux-de-Fonds, Switzerland., Penmetsa KV; Rhizen Pharmaceuticals SA, 2300 La Chaux-de-Fonds, Switzerland., Aboukameel A; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Diab M; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Kamgar M; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Al-Hallak MN; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Szlaczky M; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Tesfaye A; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Kim S; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Philip PA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Mohammad RM; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA., Azmi AS; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2020 Mar 22; Vol. 12 (3). Date of Electronic Publication: 2020 Mar 22.
DOI: 10.3390/cancers12030750
Abstrakt: Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is the first study investigating the impact of CRAC channel inhibition on PDAC cell lines and patient-derived tumor models. PDAC cell lines were exposed to a novel CRAC channel inhibitor, RP4010, in the presence or absence of standard of care drugs such as gemcitabine and nab-paclitaxel. The in vivo efficacy of RP4010 was evaluated in a hyaluronan-positive PDAC patient-derived xenograft (PDx) in the presence or absence of chemotherapeutic agents. Treatment of PDAC cell lines with single-agent RP4010 decreased cell growth, while the combination with gemcitabine/nab-paclitaxel exhibited synergy at certain dose combinations. Molecular analysis showed that RP4010 modulated the levels of markers associated with CRAC channel signaling pathways. Further, the combination treatment was observed to accentuate the effect of RP4010 on molecular markers of CRAC signaling. Anti-tumor activity of RP4010 was enhanced in the presence of gemcitabine/nab-paclitaxel in a PDAC PDx model. Our study indicates that targeting CRAC channel could be a viable therapeutic option in PDAC that warrants further clinical evaluation.
Databáze: MEDLINE
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