Pancreatic ductal adenocarcinoma is one of the most lethal human cancers; despite intense efforts, there’s just no real effective way to treat it in most patients. Cancer biologist Julien Sage, PhD, focuses his research on understanding the internal signals that tell both healthy and cancerous cells when to divide and when to chill out, and I’ve written before about his work, conducted in collaboration with biologist Or Gozani, MD, PhD, on pancreatic cancer. Now, the Sage and Gozani groups have together published a study in Genes and Development that identifies another important protein player called SMYD2. As Sage explained to me in an email:
SMYD2 is highly expressed in many cancer types and previous work in cancer cell lines suggests that SMYD2 may be pro-oncogenic. The few validated targets for SMYD2 are very intriguing, as they include proteins involved in stress responses, cell cycle checkpoints, and cancer. Based on these observations, a number of academic groups and pharmaceutical companies are developing potent and specific inhibitors of this enzyme. Strikingly, however, there are still relatively few studies on SMYD2, indicating that this seemingly central enzyme in cancer is vastly understudied.
Sage and his colleagues, including Nicolas Reynoird, PhD, a former postdoctoral scholar in the Gozani lab, and Pawel Mazur, PhD, an instructor in the Sage lab, found that SMYD2 is highly expressed in human pancreatic ductal adenocarcinomas. Furthermore, loss of SMYD2 expression slows the growth of cancer cells and reduces inflammation in a mouse model of the disease. Finally, they identified another protein called MK3 (or MAPKAPK3, for you sticklers in the audience) as a target of SMYD2 signaling. MK3 is known to promote inflammation, but this is the first time it’s been implicated in pancreatic cancer.
Taken together, the data suggest new ways to target the disease. As Sage explained:
Because a number of SMYD2 targets are involved in stress responses, we hypothesized that SMYD2 may integrate the cellular response to stress; in particular, we thought that loss of SMYD2 may impair the ability of cancer cells to evade chemotherapy. Indeed, using both a small molecule inhibitor of SMYD2 and genetic approaches, we show that blocking SMYD2 function cooperates with common chemotherapeutics to target pancreatic cancer in cellular and mouse models.
Much more research needs to be done, Sage cautions. But the study adds to a growing body of evidence that combination therapies that deliver a one-two punch to cancer cells by simultaneously targeting two or more important pathways may be the key to tackling the disease.