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Open AccessArticle

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

1
Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA
2
Rhizen Pharmaceuticals SA, 2300 La Chaux-de-Fonds, Switzerland
*
Author to whom correspondence should be addressed.
Current address: Department of Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Cancers 2020, 12(3), 750; https://doi.org/10.3390/cancers12030750
Received: 11 October 2019 / Revised: 17 March 2020 / Accepted: 17 March 2020 / Published: 22 March 2020
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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. View Full-Text
Keywords: CRAC channel; Orai1; STIM; pancreatic cancer; novel therapy CRAC channel; Orai1; STIM; pancreatic cancer; novel therapy
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Khan, H.Y.; Mpilla, G.B.; Sexton, R.; Viswanadha, S.; Penmetsa, K.V.; Aboukameel, A.; Diab, M.; Kamgar, M.; Al-Hallak, M.N.; Szlaczky, M.; Tesfaye, A.; Kim, S.; Philip, P.A.; Mohammad, R.M.; Azmi, A.S. Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth. Cancers 2020, 12, 750.

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