Metabolic Reprogramming of Pancreatic Cancer by Certain Drugs

Metabolic Reprogramming of Pancreatic Cancer by Certain Drugs

Last year, the FDA approved the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for treating a certain type of advanced breast cancer. This class of drugs has been widely studied in clinical trials for many other types of cancer, including pancreatic cancer. CDK 4/6 inhibitors are cytostatic, meaning they work by preventing cancer cells from growing and dividing.

"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.

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 -- the way cancer tumors get energy -- became more active.

Pharmacological CDK4/6 inhibitors induce cyclin D1 protein levels; however, RB activation was required and sufficient for mitochondrial accumulation.

CDK4/6 inhibition stimulated glycolytic and oxidative metabolism and was associated with an increase in mTORC1 activity. MTOR and MEK inhibitors potently cooperate with CDK4/6 inhibition in eliciting cell-cycle exit.

However, MTOR inhibition fully suppressed metabolism and yielded apoptosis and suppression of tumor growth in xenograft models.

The metabolic state mediated by CDK4/6 inhibition increases mitochondrial number and reactive oxygen species (ROS). Concordantly, the suppression of ROS scavenging or BCL2 antagonists cooperated with CDK4/6 inhibition.

The upshot is that 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.