New Biologic Vulnerability Identified in Pancreatic Cancer

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A new study is suggesting that cancer drugs known as cyclin-dependent kinase 4/6 (CDK4/6) inhibitors alter the metabolism of pancreatic cancer cells, leaving these cells to be more vulnerable to targeted agents.

The findings, which were published in Cell Reports, show that it may be possible to metabolically reprogram pancreatic cancer. The researchers found that CDK 4/6 inhibition increases oxidative phosphorylation through the retinoblastoma tumor suppressor (RB) pathway. They also demonstrated that compensatory activation of mTOR occurs downstream of CDK4/6 inhibition.

The study suggests that combination treatments for pancreatic cancer can have a variety of effects on cellular metabolism. The researchers report that it may be feasible to therapeutically target select features of CDK-arrested cells and combat cancer in a whole way.

Last year, the US Food and Drug Administration approved the first CDK4/6 inhibitor, palbociclib (Ibrance) for treating advanced breast cancer. This class of drugs has been put to the test in other various clinical trials, which now includes pancreatic cancer.

CDK 4/6 inhibitors are cytostatic, which means that these drugs work by preventing cancer cells from growing. “On the one hand, that’s great, because the tumor won’t grow, but on the other hand, the patient still has a tumor, which will eventually become resistant to those drugs,” said study senior author Erik Knudsen, MD, Professor of Internal Medicine in the Eugene McDermott Center for Human Growth and Development at University of Texas Southwestern Medical Center, in a news release.  

In this study, the research team treated human pancreatic cancer cells and tumors grown in mice with CDK4/6-inhibiting drugs. Surprisingly, they found that when tumor cells were treated with CDK4/6 inhibitors, the cells’ metabolism became more active. It is hoped that by targeting altered tumor metabolism, it may be possible to turn the cytostatic effect of CDK4/6 inhibitors into a cytotoxic effect that actually kills the cancer cells.

Study co-investigator Agnieszka Witkiewicz, MD, who is also with the McDermott Center and is an Associate Professor of Pathology, said right now there is a lot of interest in better understanding the biology behind CDK4/6 inhibitors. It is hoped this information could help lead to destroying tumors instead of simply stopping their growth.

It is theorized by disrupting a tumor’s cell cycle with CDK4/6 inhibitors and then targeting the altered metabolism with other drugs, such as mTOR inhibitors, it may be possible to positively impact cancer treatment.  “These data yield valuable new insights into the cross talk between CDK inhibitors, signaling pathways, and tumor metabolism in pancreatic cancer, opening up some interesting new possibilities for treatment that could be evaluated in clinical trials,” said Dr. Witkiewicz.