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Updated: Dec 25, 2025
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell
Husain Yar Khan1, Gabriel B Mpilla1, Rachel Sexton1
1Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Abstract:
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.
Insights
Targeting calcium release-activated calcium (CRAC) channels with RP4010 shows promise for pancreatic cancer treatment. Combining RP4010 with chemotherapy enhanced anti-tumor activity in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents significant clinical challenges requiring novel molecularly targeted therapies.
- Calcium signals, particularly via calcium release-activated calcium (CRAC) channels, are implicated in cancer progression and metastasis.
Purpose of the Study:
- To investigate the therapeutic potential of CRAC channel inhibition in PDAC.
- To evaluate the efficacy of a novel CRAC channel inhibitor, RP4010, alone and in combination with standard chemotherapy in PDAC models.
Main Methods:
- PDAC cell lines and patient-derived xenografts (PDx) were treated with RP4010, gemcitabine, and nab-paclitaxel.
- In vitro and in vivo anti-tumor efficacy was assessed.
- Molecular analyses were performed to examine CRAC signaling pathway modulation.
Main Results:
- RP4010 alone reduced PDAC cell growth.
- Combination therapy with RP4010 and gemcitabine/nab-paclitaxel demonstrated synergistic effects and enhanced anti-tumor activity in PDx models.
- RP4010 modulated CRAC signaling pathway markers, with combination treatment accentuating these effects.
Conclusions:
- CRAC channel inhibition represents a potential therapeutic strategy for PDAC.
- Further clinical evaluation of RP4010, particularly in combination regimens, is warranted for PDAC treatment.
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