Researchers Unravel the Mystery behind Drug Resistance Seen in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent neoplastic disease of the pancreas. This condition accounts for about 90% of all cancers of the pancreas worldwide. Like all cancers, this disease condition is caused by a genetic mutation that causes the rapid and uncontrollable growth of cells. Over time, scientists have attempted to understand the concept of cancers and have developed techniques to combat them; While some cancers have shown good responses to treatment, others have been quite resistant to treatment. PDAC is one of those aggressive cancers with a poor prognosis. Before now, scientists have been puzzled by the mechanism of drug resistance exhibited by neoplastic cells in PDAC. However, the mechanism has remained poorly understood until now.

Pancreas Image Courtesy of Blausen Medical

In a recent publication on bioRxiv, researchers across several institutes in Germany have discovered the mechanisms behind the drug resistance observed in cells with pancreatic ductal adenocarcinoma. They theorize that this technique would help give patients with the condition a fighting chance.

Why has pancreatic ductal adenocarcinoma always been resistant to therapy?

Usually, the MAPK pathway plays an important role in cell growth and proliferation. The pathway involves a downstream protein known as MEK. An increased expression of MEK results in growth. Usually, one of the ways the cell regulates growth is by inhibiting MEK using the MEK inhibitor MEKi. Researchers postulated that insensitivity of the MEK protein may be responsible for the resistance seen in PDAC. To better understand the basis of the lack of inhibition of the MAPK pathway noticed in cells with PDAC, researchers analyzed primary tumor cells obtained from ten PDACs of genetically engineered mice. They analyzed the gain and loss of resistance following MEKi exposure and withdrawal by longitudinal integrative analysis of whole-genome sequencing, whole-genome bisulfite sequencing, RNA-sequencing, and mass spectrometry data. They discovered that the cells escaped the effects of MEKi by adding methyl groups to their DNA (an epigenetic process known as hypermethylation). The DNA showed adaptative hypermethylation in 209 and hypomethylation in 8 genomic sites. Interestingly, most of these sites overlapped with the regulatory elements known to be active in murine PDAC cells. However, both the DNA methylation changes and MEKi resistance were momentary and reversible upon drug withdrawal.

Clinical significance

The epigenetic changes observed in PDAC result in the inhibition of about 114 genes, including Caspase 3, a gene that plays a very important role in the apoptotic process that naturally destroys cancerous cells. An understanding of this mechanism allows researchers to develop ways to reactivate this gene whose inhibition is associated with PDAC. Since caspase 3 is a primary actor in the death of cancer cells, reactivation of the CASP3 gene which codes for the protein actor will allow scientists to effectively destroy cells affected by PDAC and allow the effective management of PDAC.

Conclusion

For ages, pancreatic cancers have been feared among the list of carcinomas that plague humans; But this research proves that there may just be a way to turn this feared disease into anything but a death sentence.