New research from investigators at the Sidney Kimmel Cancer Center at Jefferson provides insight into a cellular mechanism underlying the ability of pancreatic cancer cells to resist a promising, personalized therapy. The study was recently published online in Cancer Research.
The research team studied the role of an RNA-binding protein termed HuR in influencing the sensitivity of cancer cells to treatment with a class of drugs known as PARP inhibitors. PARP inhibitors block activity of the polyADP-ribose polymerase (PARP) enzymes, which orchestrate multiple pathways dedicated to repairing damaged DNA during cell division and other cellular processes. The primary target of these drugs, the PARP1 protein, senses and initiates DNA damage repair, a process that a subgroup of pancreatic cancer cells with “BRCAness” (a DNA repair defective gene signature) are especially reliant on. Hence, PARP inhibitors are often initially effective in stalling the growth of cancers from patients with mutations in the BRCA pathway, but this effect is typically transient, as responsive tumors eventually develop resistance to inhibitors and progress to a more aggressive tumor.
In the new study, led by senior author Jonathan Brody, PhD, of the Jefferson Pancreas, Biliary, and Related Cancer Center and the Department of Surgery at Thomas Jefferson University, the team demonstrated that genetic silencing via CRISPR techniques of the HuR gene increased the relative sensitivity of pancreatic ductal adenocarcinoma (PDA) cells to PARP inhibitors. Further exploration of these effects uncovered a new target, the messenger RNA for polyADP-ribose glycohydrolase (PARG), which was stabilized by HuR when PDA cells were treated with PARP inhibitors. Brody highlighted the significance of this regulatory mechanism by explaining that “we have discovered a novel aspect of DNA repair, the regulation of a key gene (PARG) that gets turned on following DNA damage. We found that this mechanism is key for pancreatic cancer cells, but also may be important for every cell, and even normal cells.”
The functional interplay between PARP1, HuR, and PARG has important implications for developing new strategies to break chemotherapeutic resistance and treat pancreatic cancer effectively. In the presence of PARP inhibitors, increased levels of PARG mediated by HuR facilitates DNA damage repair and enables cancer cells to continue to propagate, thus developing resistance to PARP inhibitors and transforming them into a more aggressive, lethal tumor. “We believe this is an important event for how cancer cells deflect and resist common and novel therapies in the clinic. If we can target this mechanism, which we are attempting to do now, we can optimize current, promising therapies for this devastating disease. Additionally, we believe we have validated two important targets for cancer, PARG and HuR,” Brody said.
Following up on these predictions, the group examined the behavior of human PDA cells in a mouse model for pancreatic cancer. They observed that PARP inhibition combined with targeted silencing of HuR resulted in a stronger reduction in tumor growth than PARP inhibition alone, lending credence to the idea that targeting the PARP-HuR-PARG axis might yield clinical benefits in treating pancreatic cancer, as well as other cancers. Speaking on behalf of the research team that conducted the study, Brody offered a glimpse of their future plans for the project, stating that “we are further delineating this mechanism, and at the same time, we are developing therapeutic strategies, both small molecule-based and nanotherapy-based, to target this pathway in pancreatic cancer. Our ultimate goal is to move this work toward a clinical trial.”
The first author of the study, Saswati N. Chand, obtained her doctoral degree from the Jefferson Biochemistry and Molecular Biology Graduate Program and is currently a postdoctoral researcher in Dr. Brody’s laboratory in the Jefferson Pancreas, Biliary, and Related Cancer Center and the SKCC Gastrointestinal Cancer Program. Other SKCC investigators participating in the project include Drs. Eric Londin, Wei Jiang, Charles J. Yeo, Jordan M. Winter, and Karen E. Knudsen. In addition, collaborators from the Université de Montréal in Canada, the Lombardi Comprehensive Cancer Center at Georgetown University in Washington DC, and the Novartis Institute for Biomedical Research in Basel, Switzerland contributed to the research. This work was supported, in part, by an R01 grant from the National Cancer Institute, NIH.