2. Academic Validation
  3. MicroRNA-Mediated Suppression of the TGF-β Pathway Confers Transmissible and Reversible CDK4/6 Inhibitor Resistance

MicroRNA-Mediated Suppression of the TGF-β Pathway Confers Transmissible and Reversible CDK4/6 Inhibitor Resistance

  • Cell Rep. 2019 Mar 5;26(10):2667-2680.e7. doi: 10.1016/j.celrep.2019.02.023.
Liam Cornell 1,  Seth A Wander 2,  Tanvi Visal 1,  Nikhil Wagle 2,  Geoffrey I Shapiro 3
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: geoffrey_shapiro@dfci.harvard.edu.
PMID: 30840889 DOI: 10.1016/j.celrep.2019.02.023
Abstract

CDK4/6 inhibition is now part of the standard armamentarium for patients with estrogen receptor-positive (ER+) breast Cancer, so that defining mechanisms of resistance is a pressing issue. Here, we identify increased CDK6 expression as a key determinant of acquired resistance after palbociclib treatment in ER+ breast Cancer cells. CDK6 expression is critical for cellular survival during palbociclib exposure. The increased CDK6 expression observed in resistant cells is dependent on TGF-β pathway suppression via miR-432-5p expression. Exosomal miR-432-5p expression mediates the transfer of the resistance phenotype between neighboring cell populations. Levels of miR-432-5p are higher in primary breast cancers demonstrating CDK4/6 resistance compared to those that are sensitive. These data are further confirmed in pre-treatment and post-progression biopsies from a parotid Cancer patient who had responded to ribociclib, demonstrating the clinical relevance of this mechanism. Finally, the CDK4/6 inhibitor resistance phenotype is reversible in vitro and in vivo by a prolonged drug holiday.

Keywords

CDK6; SMAD4; TGF-β; breast cancer; drug resistance; exosomes; microRNA; palbociclib; ribociclib; targeted therapy.

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