Details

Autor(en) / Beteiligte

• de Leeuw, Renée
• McNair, Christopher
• Schiewer, Matthew J
• Neupane, Neermala Poudel
• Brand, Lucas J
• Augello, Michael A
• Li, Zhen
• Cheng, Larry C
• Yoshida, Akihiro
• Courtney, Sean M
• Hazard, E Starr
• Hardiman, Gary
• Hussain, Maha H
• Diehl, J Alan
• Drake, Justin M
• Kelly, Wm Kevin
• Knudsen, Karen E

Titel

MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer

Ist Teil von

• Clinical cancer research, 2018-09, Vol.24 (17), p.4201-4214

Ort / Verlag

United States

Erscheinungsjahr

2018

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• Loss of cell-cycle control is a hallmark of cancer, which can be targeted with agents, including cyclin-dependent kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G -S cell-cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon. In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer. This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive and phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phosphoproteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive and phenotypes and prometastatic signaling. However, CDK4/6 inhibitor-resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion. In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer. .