Semantic Scholar Open Access 2016 182 sitasi

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

J. Franco U. Balaji Elizaveta Freinkman A. Witkiewicz Erik S. Knudsen

Lihat Sumber DOI

Abstrak

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.

Topik & Kata Kunci

Medicine Biology

Penulis (5)

J. Franco

U. Balaji

Elizaveta Freinkman

A. Witkiewicz

Erik S. Knudsen

Format Sitasi

APA MLA BibTeX

Franco, J., Balaji, U., Freinkman, E., Witkiewicz, A., Knudsen, E.S. (2016). Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities.. https://doi.org/10.1016/j.celrep.2015.12.094

Akses Cepat

Lihat di Sumber doi.org/10.1016/j.celrep.2015.12.094

Informasi Jurnal

Tahun Terbit: 2016
Bahasa: en
Total Sitasi: 182×
Sumber Database: Semantic Scholar
DOI: 10.1016/j.celrep.2015.12.094
Akses: Open Access ✓