Knock out a genetic mutation that’s a driving force behind pancreatic cancer and a few cells quietly hunker down in the resulting scar tissue, nibbling on themselves to survive before roaring back as resistant disease that taps the cell’s normal powerhouses to thrive.
Scientists at The University of Texas MD Anderson Cancer Center reveal this mode of metabolic resistance to targeted cancer therapy and a way to attack it in a paper published online in Nature.
Their findings raise the possibility of combining a drug that inhibits the function of mitochondria, the cell’s main energy producers, with targeted therapies to thwart pancreatic cancer recurrence.
“Effective therapies that target specific genes can have an incredible initial impact. Cancerous lesions disappear, but they all come back, all of them,” said senior author Giulio Draetta, Ph.D., M.D., professor of Molecular and Cellular Biology. “So there must be something left behind. We’re interested in what’s left behind.”
“Targeting mitochondrial function with drugs called OXPHOS inhibitors to overcome resistance to targeted therapies would be an entirely new paradigm in cancer treatment,” said Draetta, also a professor of Genomic Medicine.
Surviving without KRAS
Draetta said Andrea Viale, Ph.D., instructor in Genomic Medicine and lead author of the paper, wanted to know whether tumor-initiating pancreatic cancer stem cells need an active oncogene to survive.
The scientists’ research focused on KRAS, a gene whose mutated versions are known to drive development and progression of pancreatic ductal adenocarcinoma, largely incurable cancer with only a 6 percent survival rate at five years.
They developed a unique mouse model that allows them to induce KRAS-driven pancreatic cancer and then turn KRAS 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 4-5 months with KRAS still turned off.
Nests of surviving cells were found in fibrotic scar tissue left after KRAS-deprived tumors appeared to completely regress.
“The surviving cells were dormant, and there was lots of autophagy – essentially they were eating pieces of themselves,” Draetta said. The survivors had many characteristics of pancreatic cancer stem cells.
Metabolic differences, not genetic mutations, drive resistance
Additional analysis showed that the resistant cells did not arise via genetic selection of new dominant mutations after KRAS was gone.
Instead, there was strong expression of genes that govern mitochondrial function and mitochondrial respiration. Cellular mitochondria are the main metabolic power plants of the cell, using 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.
OXPHOS and KRAS inhibition work together
The team 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 tumor spheres 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 said the 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.
Draetta and collaborator Lewis Cantley, Ph.D., Joan and Sanford I. Weill Medical College of Cornell University, New York, were awarded a three-year, $1 million grant earlier this year by the Pancreatic Cancer Action Network and the American Association for Cancer Research titled “Developing a novel oxidative phosphorylation inhibitor in pancreatic cancer.”
“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’ performance status.”
Co-authors with Viale and Draetta are co-lead author Piergiorgio Pettazzoni, Haoqiang Ying, Nora Sanchez, Matteo Marchesini, Alessandro Carugo, Tessa Green, Florian Muller, Simona Colla, Luigi Nez, Giannicola Genovese, Angela K. Deem, Avnish Kapoor, Wantong Yao and Y. Alan Wang of Medical Genomics; Costas Lyssiotis and Cantley of Weill Cornell Medical College, New York; Sahil Seth, Virginia Giuliani, Maria Kost-Alimova, and Timothy Heffernan of MD Anderson’s Institute for Applied Cancer Science; Emanuela Brunetto of San Raffaele Scientific Institute, Milan, Italy; Ya’an Kang and Jason Fleming of Surgical Oncology at MD Anderson; Min Yuan, and John M. Asara of Beth Israel Deaconness Hospital, Boston; Alec Kimmelman of Dana-Farber Cancer Institute, Boston; Huamin Wang MD Anderson Pathology; and Ronald DePinho, MD Anderson Cancer Biology.
This research was funded by the Hirshberg Foundation for Pancreatic Cancer Research, the Harvard Stem Cell Institute, Sheikh Ahmed Center for Pancreatic Cancer Research at MD Anderson, American Italian Cancer Foundation, The National Cancer Institute of the National Institutes of Health (P01CA117969, NCI P01CA120964), The Viragh Family Foundation, a Pancreatic Cancer Action Network-AACR Pathway to Leadership Fellowship and MD Anderson’s NCI Cancer Center Support Grant (CA16672).