Outwitting resistant pancreatic cancer

Knock out a mutated gene that’s a driving force behind pancreatic cancer and a few cancer cells quietly remain behind, where they hunker down in the resulting scar tissue and nibble on themselves to survive before roaring back as resistant pancreatic cancer.

“Therapies that target specific, mutated genes can have an incredible initial impact. Cancerous lesions disappear, but they all come back, all of them,” said Giulio Draetta, Ph.D., M.D., professor in Molecular and Cellular Oncology and Genomic Medicine and senior author of an article in Nature that describes this cell-survival process. “So there must be something left behind. We’re interested in what’s left behind.”

To answer this question, Draetta and Andrea Viale, Ph.D., instructor in Genomic Medicine and lead author of the paper, first needed to know whether pancreatic cancer stem cells that result in tumors require an active oncogene (a gene that causes the transformation of normal cells into cancerous cells) to survive.

The scientists’ research focused on KRAS, a gene whose mutated versions are known to fuel pancreatic ductal adenocarcinoma, which accounts for 90% of all pancreatic cancers and has only a 6% survival rate at five years.

They induced KRAS-driven pancreatic cancer in experimental mice, then turned the KRAS gene off. The mice are genetically engineered so that treating them with the antibiotic doxycycline activates KRAS expression in the pancreas. When the researchers withdrew doxycycline, tumors regressed in two or three weeks, but then returned in four or five months with KRAS still turned off.

Nests of surviving cells that had many characteristics of pancreatic cancer stem cells were found in scar tissue left after KRAS-deprived tumors appeared to completely subside.

“The surviving cells were dormant, and there was lots of autophagy — essentially they were eating pieces of themselves,” Draetta said.

Additional analysis showed that the resistant cells didn’t arise via genetic selection of new dominant mutations after KRAS was gone.

Instead, there was strong expression of genes that govern the function and respiration of mitochondria — the cell’s main energy producers. Mitochondria use oxygen to convert fatty acids and proteins into energy by a process of oxidative phosphorylation (OXPHOS).

The resistant cells also relied less on another method of energy production called glycolysis, the conversion of glucose to energy in the absence of oxygen, which is commonly found in cancer.

“We suspected that this reliance on mitochondrial respiration made these resistant tumors vulnerable to OXPHOS inhibitors,” Draetta said.

The researchers found that treating resistant cells and KRAS-dependent cells with the OXPHOS inhibitor oligomycin reduced mitochondrial respiration in both cell types. While KRAS-dependent cells made up for the energy loss by increasing glycolysis, the survivor cells could not compensate for the resulting energy deficit.

Subsequent experiments showed that oligomycin treatment reduced the ability of cells to form tumors and increased the survival of mice.

KRAS so far cannot be directly targeted by a drug, but two pathways that it regulates — MEK and PI3K — can. Draetta and collaborators are studying combinations of MEK, PI3K and OXPHOS inhibitors as well as moving OXPHOS drugs toward the clinic. MD Anderson’s Institute of Applied Cancer Science is developing an OXPHOS inhibitor.

“This approach will need to be managed carefully because mitochondrial function is required for many vital functions,” Draetta said. So far, preclinical studies indicate this can be done safely, but the next step is to undertake formal toxicology studies. “We need to be cautiously optimistic at this point.

“We’re excited that we aren’t just targeting the proliferating cells in a tumor,” Draetta said. “A large portion of a tumor doesn’t proliferate, it’s just sitting there dormant, making a mess and secreting harmful cytokines that affect patients’ health.”