Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6

Cancer Res. 2016 May 15;76(10):2990-3002. doi: 10.1158/0008-5472.CAN-15-2931. Epub 2016 Mar 17.

Abstract

Dysregulation of the p16-cyclin D1-CDK4/6-Rb pathway occurs frequently in melanoma; however, the therapeutic efficacy of CDK4/6 inhibition remains to be critically evaluated. We demonstrate that CDK4/6 inhibition inhibits melanoma progression through induction of senescence. Palbociclib, a specific CDK4/6 inhibitor, rapidly induces cell cycle arrest within 24 hours and continued exposure for 8 days or longer induces senescence. The induction of senescence correlates with inhibition of mTOR and more specifically mTORC1 signaling. Vemurafenib, a specific BRAF(V600E) inhibitor, has significant clinical efficacy in BRAF(V600E)-positive melanomas, but its impact is hampered by a rapid acquisition of resistance. Strikingly, we found that vemurafenib-resistant tumors remain sensitive to palbociclib, suggesting that initial treatment with vemurafenib followed by palbociclib with or without mTOR inhibitors might provide an avenue to overcome recurrence of vemurafenib-resistant metastatic disease. Taken together, these results support palbociclib as a promising therapeutic for treatment of melanoma. Cancer Res; 76(10); 2990-3002. ©2016 AACR.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects*
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Drug Resistance, Neoplasm / drug effects*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immunoenzyme Techniques
  • Indoles / pharmacology*
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Mice, SCID
  • Mutation / genetics
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / genetics
  • Pyridines / pharmacology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured
  • Vemurafenib
  • Xenograft Model Antitumor Assays

Substances

  • Indoles
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • RNA, Messenger
  • Sulfonamides
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • palbociclib