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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth major cause of cancer-associated mortality in the United States of America (USA)
Vs. 18.7 μM), indicating that the effect of RP4010 on the proliferation of pancreatic cancer cells mainly stems from its ability to inhibit calcium release-activated calcium (CRAC) channel
In this paper we report, for the first time, that targeting the CRAC channel by small molecule drug RP4010 suppresses the growth of PDAC cell lines, and patient-derived tumors
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth major cause of cancer-associated mortality in the United States of America (USA). The current 5-year survival rate for PDAC stands at a meager. PDAC is a lethal disease with currently no reliable screening methods to detect it in premalignant or early stages. Cancers 2020, 12, 750 stage, when the disease has metastasized. This further undermines the success of any treatment. Since surgical resection of PDAC is not feasible in the majority of the cases, radiotherapy and chemotherapy remain the only viable treatment options. In the majority of cases, patients develop resistance, which makes identifying novel cellular and molecular targets and better drugs to treat PDAC even more important
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