Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities

• DOI: 10.1016/j.celrep.2015.12.094
• Publication Date: 2016-01-21T22:05:28Z
• Authors: Jorge Franco; Uthra Balaji; Elizaveta Freinkman; Agnieszka K. Witk...; Erik S. Knudsen
• Keywords: QH301-705.5; TOR Serine-Threonine Kinases; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Retinoblastoma Protein; Article; Mitochondria; 3. Good health; Pancreatic Neoplasms; Cell Line, Tumor; Humans; Biology (General); Reactive Oxygen Species; Protein Kinase Inhibitors; Signal Transduction

Due to loss of p16ink4a in pancreatic ductal adenocarcinoma (PDA), pharmacological suppression of CDK4/6 could represent a potent target for treatment. In PDA models, CDK4/6 inhibition had a variable effect on cell cycle but yielded accumulation of ATP and mitochondria. 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. Together, these data define the impact of therapeutics on PDA metabolism and provide strategies for converting cytostatic response to tumor cell killing.