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

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

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2019;24(17):4201-4214

PMID: 29739788

Free Full Text on PubMed Central View on PubMed

Abstract

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. .

Address: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.; Graduate Program in Cellular and Molecular Pharmacology, School of Graduate Studies, Rutgers, The State University of New Jersey, Piscataway, New Jersey.; Graduate Program in Quantitative Biomedicine, School of Graduate Studies, Rutgers, The State University of New Jersey, Piscataway, New Jersey.; Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.; Center for Genomic Medicine Bioinformatics, Medical University of South Carolina (MUSC), Charleston, South Carolina.; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.; Library Science and Informatics, Medical University of South Carolina, Charleston, South Carolina.; Departments of Medicine and Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.; Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois.; Division of Medical Oncology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.; Department of Medical Oncology, Urology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. [email protected].; Sidney Kimmel Cancer Center, Thomas Jefferon University, Philadelphia, Pennsylvania.

DOI: 10.1158/1078-0432.CCR-18-0410