University of North Carolina Lineberger Comprehensive Cancer Center researchers reported the discovery of a potential treatment strategy to reduce resistance to a chemotherapy combination used to treat pancreatic cancer, one of the deadliest cancer types.
UNC Lineberger’s Jen Jen Yeh, MD, professor in the UNC School of Medicine Departments of Surgery and Pharmacology and vice chair of research in the Department of Surgery, and Matthew Lipner, medical and doctoral student in the UNC School of Medicine, reported in JCI Insight that a small molecule called JNK-IN-8, a JNK inhibitor, worked synergistically with the combination chemotherapy regimen folfox in preclinical studies of pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer.
“Chemotherapies are considered or used in nearly every case of pancreatic adenocarcinoma, but there is limited understanding of the complex signaling responses underlying the high level of resistance that limits the efficacy of these common treatments,” Lipner said. “Unbiased approaches such as ours to design rational combination therapies may reveal therapeutically exploitable vulnerabilities in pancreatic and other cancers that can be used to improve patient outcomes for these deadly cancers.”
In the study, researchers profiled changes to cellular proteins in laboratory models of pancreatic cancer after treatment with chemotherapy.
They studied the patterns of proteins to understand changes the chemotherapy regimen was having on the cell, and potential protein signals that were helping to drive the cancer.
The researchers then screened a library of chemical compounds in order to identify treatments that showed potential to block the proteins they saw emerged in the pancreatic cancer models after drug treatment.
“This study highlights the potential for JNK-IN-8 and other novel irreversible kinase inhibitors as biological tools to better understand kinase signaling in cancer and as components of possible combination therapies,” Lipner said. “Future work is needed to continue to elucidate the mechanism underlying synergy between JNK-IN-8 and chemotherapeutic agents as well as to more fully maximize the drug combination’s in vivo antitumor effects.”
Authors and Disclosures
In addition to Lipner and Yeh, other authors included X.L. Peng: C. Jin; Y. Gao; M.P. East; N.U. Rashid; R.A. Moffitt; S.G. Herrera-Loeza; A.B. Morrison; B.T. Golitz; C. Vaziri; L.M. Graves; and G.L. Johnson.
The study was supported by the National Institutes of Health. Individual researchers were supported by the National Institutes of Health and a UNC School of Medicine Department of Pharmacology Training Grant.