MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer.

Authors

Renée de Leeuw, Thomas Jefferson UniversityFollow
Christopher McNair, Thomas Jefferson UniversityFollow
Matthew J. Schiewer, Thomas Jefferson UniversityFollow
Neermala Poudel Neupane, Thomas Jefferson UniversityFollow
Lucas J. Brand, Thomas Jefferson University
Michael A. Augello, Thomas Jefferson UniversityFollow
Zhen Li, Rutgers Cancer Institute of New Jersey
Larry C. Cheng, Rutgers Cancer Institute of New Jersey; Rutgers, State University of New Jersey
Akihiro Yoshida, Medical University of South Carolina
Sean M. Courtney, Medical University of South Carolina
E. Starr Hazard, Medical University of South Carolina
Gary Hardiman, Medical University of South Carolina
Maha H. Hussain, Northwestern University
J. Alan Diehl, Medical University of South Carolina
Justin M. Drake, Rutgers Cancer Institute of New Jersey; Rutgers, State University of New Jersey; Rutgers Robert Wood Johnson Medical School
William Kevin Kelly, Thomas Jefferson UniversityFollow
Karen E. Knudsen, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

9-1-2018

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Clinical Cancer Research, Volume 24, Issue 17, September 2018, Pages 4201-4214.

The published version is available at https://doi.org/10.1158/1078-0432.CCR-18-0410. Copyright © American Association for Cancer Research

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 G₁-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.

Recommended Citation

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, William Kevin; and Knudsen, Karen E., "MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer." (2018). Department of Cancer Biology Faculty Papers. Paper 156.
https://jdc.jefferson.edu/cbfp/156

PubMed ID

29739788

Language

English