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

Jorge Franco, Uthra Balaji, Elizaveta Freinkman, Agnieszka K. Witkiewicz, Erik S. Knudsen

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)979-990
Number of pages12
JournalCell Reports
Volume14
Issue number5
DOIs
StatePublished - Feb 9 2016

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Pancreatic Neoplasms
Metabolism
Enzyme inhibition
Adenocarcinoma
Cells
Tumors
Reactive Oxygen Species
Cell Cycle
Pharmacology
Mitochondria
Cyclin D1
Scavenging
Mitogen-Activated Protein Kinase Kinases
Cytostatic Agents
Heterografts
Neoplasms
Adenosine Triphosphate
Chemical activation
Apoptosis
Growth

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities. / Franco, Jorge; Balaji, Uthra; Freinkman, Elizaveta; Witkiewicz, Agnieszka K.; Knudsen, Erik S.

In: Cell Reports, Vol. 14, No. 5, 09.02.2016, p. 979-990.

Research output: Contribution to journalArticle

Franco, Jorge ; Balaji, Uthra ; Freinkman, Elizaveta ; Witkiewicz, Agnieszka K. ; Knudsen, Erik S. / Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities. In: Cell Reports. 2016 ; Vol. 14, No. 5. pp. 979-990.
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