Combined blockade of MEK and CDK4/6 pathways induces senescence to improve survival in pancreatic ductal adenocarcinoma

Brent A. Willobee, Alexander A. Gaidarski, Austin R. Dosch, Jason A. Castellanos, Xizi Dai, Siddharth Mehra, Fanuel Messaggio, Supriya Srinivasan, Michael N. VanSaun, Nagaraj S. Nagathihalli, Nipun B. Merchant

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Activating KRAS mutations, a defining feature of pancreatic ductal adenocarcinoma (PDAC), promote tumor growth in part through the activation of cyclin-dependent kinases (CDK) that induce cell-cycle progression. p16INK4a (p16), encoded by the gene CDKN2A, is a potent inhibitor of CDK4/6 and serves as a critical checkpoint of cell proliferation. Mutations in and subsequent loss of the p16 gene occur in PDAC at a rate higher than that reported in any other tumor type and results in Rb inactivation and unrestricted cellular growth. Therefore, strategies targeting downstream RAS pathway effectors combined with CDK4/6 inhibition (CDK4/6i) may have the potential to improve outcomes in this disease. Herein, we show that expression of p16 is markedly reduced in PDAC tumors compared with normal pancreatic or pre-neoplastic tissues. Combined MEK inhibition (MEKi) and CDK4/6i results in sustained downregulation of both ERK and Rb phosphorylation and a significant reduction in cell proliferation compared with monotherapy in human PDAC cells. MEKi with CDK4/6i reduces tumor cell proliferation by promoting senescence-mediated growth arrest, independent of apoptosis in vitro. We show that combined MEKi and CDK4/6i treatment attenuates tumor growth in xenograft models of PDAC and improves overall survival over 200% compared with treatment with vehicle or individual agents alone in Ptf1acre/+;LSL-KRASG12D/+;Tgfbr2flox/flox (PKT) mice. Histologic analysis of PKT tumor lysates reveal a significant decrease in markers of cell proliferation and an increase in senescence-associated markers without any significant change in apoptosis. These results demonstrate that combined targeting of both MEK and CDK4/6 represents a novel therapeutic strategy to synergistically reduce tumor growth through induction of cellular senescence in PDAC.

Original languageEnglish
Pages (from-to)1246-1256
Number of pages11
JournalMolecular Cancer Therapeutics
Volume20
Issue number7
DOIs
StatePublished - Jul 2021

Keywords

  • Animals
  • Carcinoma, Pancreatic Ductal/drug therapy
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Cell Survival/drug effects
  • Cellular Senescence/drug effects
  • Cyclin-Dependent Kinase 4/antagonists & inhibitors
  • Cyclin-Dependent Kinase 6/antagonists & inhibitors
  • Disease Models, Animal
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic
  • Genes, p16
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Kinases/metabolism
  • Protein Kinase Inhibitors/pharmacology
  • Signal Transduction/drug effects
  • Xenograft Model Antitumor Assays

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