MAPK Reliance via acquired CDK4/6 inhibitor resistance in cancer

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

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Purpose: 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 1 –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. Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer. Results: This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo 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 in vitro and in vivo 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)4201-4214
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number17
Early online date08 May 2018
DOIs
Publication statusPublished - 01 Sep 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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