Understanding Chemotherapy Resistance in Pancreatic Cancer



Glutamine withdrawal induced HuR translocation from the nucleus to the cytoplasm in MiaPaCa2 parental cells, as detected by immunofluorescence.

A collaborative study involving Sidney Kimmel Cancer Center at Jefferson (SKCC) investigators, together with colleagues from the University of California at San Diego, has provided important insights into how pancreatic cancer cells are able to resist the effects of chemotherapeutic agents. The new study, published in Cancer Research, was led by senior author Jordan Winter, MD, FACS, Associate Professor of Surgery at Jefferson.

The investigators uncovered a regulatory mechanism that helps pancreatic cells survive the harsh, nutrient-deprived microenvironment of the tumor, and also confers protection against the chemotherapy drugs that are designed to eliminate these cancer cells. The lead author, postdoctoral fellow Mahsa Zarei, PhD, of the Winter laboratory, and her colleagues found that the chemoresistance was driven by the RNA-binding protein HuR, which induces expression of the antioxidant enzyme isocitrate dehydrogenase 1 (IDH1), thereby altering the metabolism of the cancer cells and allowing them to better tolerate both their harsh microenvironment as well as the chemotherapy drugs.

“We found that the same mechanisms that enable pancreatic cancer to survive its desert-like environment also protect the cells against the drugs we use to treat patients,” Winter said. Identifying this cellular mechanism that contributes to pancreatic cell chemoresistance holds promise for developing effective treatment strategies that will neutralize the mechanism and thereby render pancreatic cancer cells more sensitive to chemotherapy, with the ultimate goal of improving patient outcomes. “We hope that understanding how this works at a molecular level will enable us to develop therapies against these survival pathways while sparing normal cells that do not rely on them,” Winter added.

In addition to Winter, other SKCC investigators contributing to the study included Drs. Wei Jiang, Charles Yeo, Eric Londin, Erin Seifert, and Jonathan Brody.

For further details, see:  Mahsa Zarei, Shruti Lal, Seth J. Parker, Avinoam Nevler, Ali Vaziri-Gohar, Katerina Dukleska, Nicole C. Lisboa, Cynthia Moffat, Fernando F. Blanco, Saswati N. Chand, Masaya Jimbo, Joseph A. Cozzitorto, Wei Jiang, Charles J. Yeo, Eric R. Londin, Erin L. Seifert, Christian M. Metallo, Jonathan R. Brody, and Jordan M. Winter. 2017. Posttranscriptional upregulation of IDH1 by HuR establishes a powerful survival phenotype in pancreatic cancer cells. Cancer Research. doi:10.1158/0008-5472.CAN-17-0015. Published January 2017.