CDK4/6 Inhibition on Glucose and Pancreatic Beta Cell Homeostasis in Young and Aged Rats

• Published in: Molecular cancer research 2017-11, Vol.15 (11), p.1531-1541
• Main Authors: Sacaan, Aida I, Thibault, Stephane, Hong, Miyoun, Kondegowda, Nagesha G, Nichols, Tim, Li, Rosemary, Rosselot, Carolina, Evering, Winston, Fenutria, Rafael, Vitsky, Allison, Brown, Thomas, Finkelstein, Martin, Garcia-Ocaña, Adolfo, Khan, Nasir, Stewart, Andrew F, Vasavada, Rupangi C
• Format: Article
• Language: English
• Subjects: Aging - drug effects; Aging - metabolism; Animal behavior; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Beta cells; Breast cancer; Cancer; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Cellular stress response; Children; Chronic toxicity; Clonal deletion; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase 6 - metabolism; Degeneration; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Glucose; Glucose - metabolism; Glucose tolerance; Histology; Homeostasis; Homeostasis - drug effects; Inhibition; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Kinases; Male; Metabolism; Pancreas; Piperazines - administration & dosage; Piperazines - adverse effects; Pyridines - administration & dosage; Pyridines - adverse effects; Rats; Rats, Sprague-Dawley; Rodents; Toxicity
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-17-0172

Genetic deletion of cyclin-dependent kinase 4 ( ) is associated with pancreatic beta cell loss and glucose dysregulation in rodents. Palbociclib, one of the first selective CDK4/6 inhibitors approved for the treatment of advanced breast cancer, is currently being investigated as an adjuvant treatment in patients with early-stage breast cancer and in a variety of cancers covering a wide-range of patient populations. Hence, longer chronic toxicity studies were necessary to further examine its safety profile. The effects of different doses and duration of palbociclib administration on glucose and beta cell homeostasis in young (two months) versus aged (12 months) rats was compared. Glucose dysregulation, due to pancreatic beta cell degeneration, was observed in young rats administered the highest dose of palbociclib for 6 months. Abnormal pancreatic islet histology and activation of the endoplasmic reticulum stress response in beta cells were detected after shorter administration with high-dose palbociclib in young rats. To test the hypothesis that palbociclib-associated inhibition of beta cell proliferation will more profoundly affect younger animals that have not achieved replicative quiescence, we administered high-dose palbociclib to aged rats for 6 months. In contrast to the young rats, despite equivalent exposures to palbociclib, no evidence of impaired glucose tolerance, hypoinsulinemia, beta cell vacuolization, or beta cell loss was seen in aged rats. Palbociclib administration induces beta cell failure in young but not aged rats. Although adult humans receiving palbociclib have not displayed detectable adverse effects on glucose metabolism, the risk of beta cell failure in children remains unexplored. .