NAD depletion by IFN sensitises pancreatic cancer to NAMPT inhibition, study shows
High IFN signalling in pancreatic tumours are sensitive to NAMPT inhibitors which block a pathway in NAD synthesis, presenting a drug target.
Researchers have uncovered a potential new way to target pancreatic tumours that express high intratumoural interferon signalling (IFN). The team found that high type I IFN signalling is present in a subset of pancreatic tumours and it triggers a decrease in the level of NAD and NADH in pancreatic cancer cells. The study was conducted at the University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, US.
Cancer cells use require NAD or NADH as a cofactor to transform nutrients from the environment into building blocks for cellular processes.
The team first used cell lines and cell culture to determine the mechanism of NAD depletion induced by IFN signalling by looking at the messenger RNA (mRNA) levels of NAD-consuming enzymes after treatment with IFN. There was an increase in mRNA levels as well as protein expression of PARP9, PARP10 and PARP14. They demonstrated that cells with high IFN signalling were more sensitive to NAMPT inhibitors, which inhibit a major pathway in NAD synthesis. Based on this mechanism, the researchers say that recently developed second-generation NAMPT inhibitors could potentially be used in combination with new systemic drugs, called STING agonists, which increase type I IFN signalling.
After confirming the findings, the team translated the research into an in vivo model. Researchers used two different mouse models and injected cancer cells into the pancreas of mice prior to treatment. When tested in mice, the combination of IFN signalling and NAMPT inhibitors not only decreased pancreatic tumour growth, but also resulted in fewer liver metastases.
According to the researchers, the findings provide evidence that if tumours with high IFN signalling can be identified or if IFN signalling can be amplified in tumour cells, those tumours may have greater sensitivity to treatment with NAMPT inhibitors. If so, the combination could potentially help improve the prognosis for one of the most difficult cancers to treat.
“With the advent of these two new and improved therapeutics, our findings are timely as their combination may sensitise tumours to NAD depletion,” said lead author Dr Alexandra Moore.
“This is a study that identifies a potential vulnerability created by type I IFNs in pancreatic cancer that can be leveraged for what appears to be an effective therapeutic strategy,” said senior author Dr Timothy Donahue.
The study was published in PNAS.