A new discovery about pancreatic cancer sheds light on how the cancer fuels its growth and may help explain how promising cancer drugs work - and for whom they will fail.

The finding one day could help doctors determine which treatments will be most effective for patients, so that they get the best outcomes.

Scientists previously have noted strange changes in the shape of mitochondria, the powerhouses of cells, in cancers driven by mutations in the RAS gene. The authors wanted to understand what was occurring and how it affected pancreatic cancer's growth.

The authors found that when the mutated RAS gene gets activated, it causes the mitochondria to fragment. This fragmentation supports the earliest shifts toward the cancer's new fueling process. This was quite surprising, because suddenly the mitochondria were playing a very unusual role. Their division was actually helping the cancer establish itself and helps in tumor growth through Erk phosphorylation of the mitochondrial fission GTPase Dynamin-related protein 1 (Drp1).

But there's good news: This process could prove to be a weakness for the cancer that doctors could exploit to help patients. The authors found that blocking mitochondrial division in tumor samples largely prevented the tumors from growing. And when they did grow, the cancer cells gradually lost mitochondrial function. This was bad for the cancer, and the loss of mitochondria represents another weakness doctors could exploit.

"This mitochondrial fragmentation is really playing two distinct roles: On the one hand, it's promoting this shift in metabolism. But it's also promoting mitochondrial health," the senior author said. "These two things are combining to drive the pancreatic tumor growth process. So I think this is something that could be therapeutically valuable. But it also really teaches us about pancreatic tumor growth in general."

The authors show that Drp1 is required for KRas-driven anchorage-independent growth in fibroblasts and patient-derived pancreatic cancer cell lines, and it promotes glycolytic flux, in part through the regulation of hexokinase 2 (HK2). Furthermore, Drp1 deletion imparts a significant survival advantage in a model of KRas-driven pancreatic cancer, and tumors exhibit a strong selective pressure against complete Drp1 deletion. Rare tumors that arise in the absence of Drp1 have restored glycolysis but exhibit defective mitochondrial metabolism.

The finding also may help explain the workings of several drugs in development, and it could help doctors understand which patients they will benefit, said the senior author.

"Inhibiting [mitochondrial division in patients' cancer cells] would be a nice future goal for us. However, the drugs targeting this process are really very early in development, and so it's not something that will really be ready for the clinic anytime soon,"the author said. "But this work can really help us understand how some of these other drugs that are a little bit further along in the process may be acting, so that we can better understand which patients may or may not benefit."

https://newsroom.uvahealth.com/2019/09/26/pancreatic-cancer-discovery-reveals-how-the-aggressive-cancer-fuels-its-growth/

https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30928-3

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fdrp1-promotes-kras&filter=22