Presenter: Daniel Principe
Mentor: Ajay Rana, PhD
Gemcitabine Resistance Requires the Sustained Uptake of Calcium via L-Type Channels and is Reversed by High Dose Amlodipine
Gemcitabine is among the most widely used medications in the treatment of pancreatic cancer. While Gemcitabine-based chemotherapy modestly prolongs survival in both localized and disseminated disease, nearly all tumors either have or will develop some degree of drug resistance. With no approved medications for patients who progress on chemotherapy, the aim of this study was to identify the cellular mechanisms that allow tumor cells to resist Gemcitabine in hopes of exploiting them for therapy.
Using single cell RNA sequencing and whole proteome analysis, Principe and his colleagues found that Gemcitabine resistance is dependent on the ability of tumor cells to take up large amounts of extracellular calcium. The cells then use this influx of calcium to activate the protein Calmodulin to enhance pro-survival signaling. The research discovered that by either disrupting the ability of Calmodulin to sense calcium, or by starving tumor cells of calcium using a chelator, the most resistant of cell lines to Gemcitabine could be re-sensitized.
Researchers also discovered that this increased uptake of calcium was mediated by L-Type Channels, a major drug target in cardiovascular medicine. Millions of people use inhibitors of L-Type Calcium Channels (commonly referred to as a calcium channel blocker) to control their high blood pressure. “These medications are widely available, inexpensive, and safe”, Principe said. Using a high dose of the channel blocker Amlodipine reversed Gemcitabine resistance in vitro, as well as and in orthotopic xenograft models.
Amlodipine significantly extended the duration that genetically modified mouse models of advanced pancreatic cancer responded to Gemcitabine, increasing survival from an average of four to five months to as long as 13 months, Principe said.
Combined, the results suggest that the acquisition and maintenance of Gemcitabine resistance requires sustained calcium/Calmodulin signaling, which is mediated by L-Type Calcium Channels. For the first time, Rana’s lab showed that the addition of widely available, well-tolerated, low cost agents such as Amlodipine may improve drug responses in the clinical management of pancreatic cancer.