Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway

  • Cancer Cell. 2020 Jan 13;37(1):104-122.e12. doi: 10.1016/j.ccell.2019.12.006.
Kari J Kurppa  1 ,  Yao Liu  2 ,  Ciric To  1 ,  Tinghu Zhang  2 ,  Mengyang Fan  2 ,  Amir Vajdi  3 ,  Erik H Knelson  1 ,  Yingtian Xie  4 ,  Klothilda Lim  4 ,  Paloma Cejas  4 ,  Andrew Portell  5 ,  Patrick H Lizotte  5 ,  Scott B Ficarro  6 ,  Shuai Li  7 ,  Ting Chen  7 ,  Heidi M Haikala  1 ,  Haiyun Wang  8 ,  Magda Bahcall  1 ,  Yang Gao  9 ,  Sophia Shalhout  10 ,  Steffen Boettcher  11 ,  Bo Hee Shin  1 ,  Tran Thai  1 ,  Margaret K Wilkens  12 ,  Michelle L Tillgren  12 ,  Mierzhati Mushajiang  1 ,  Man Xu  5 ,  Jihyun Choi  1 ,  Arrien A Bertram  1 ,  Benjamin L Ebert  13 ,  Rameen Beroukhim  14 ,  Pratiti Bandopadhayay  15 ,  Mark M Awad  1 ,  Prafulla C Gokhale  16 ,  Paul T Kirschmeier  5 ,  Jarrod A Marto  6 ,  Fernando D Camargo  10 ,  Rizwan Haq  17 ,  Cloud P Paweletz  5 ,  Kwok-Kin Wong  7 ,  David A Barbie  1 ,  Henry W Long  4 ,  Nathanael S Gray  2 ,  Pasi A Jänne  18
Affiliations
  • 1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • 2. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 3. Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 6. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
  • 7. Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  • 8. School of Life Science and Technology, Tongji University, 200092 Shanghai, China.
  • 9. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA.
  • 10. Stem Cell Program, Boston Children's Hospital, Boston, MA 02215, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • 11. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 12. Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
  • 13. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 14. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 15. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA.
  • 16. Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
  • 17. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 18. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, LC4114, Boston, MA 02215, USA. Electronic address: [email protected].
PMID: 31935369 DOI: 10.1016/j.ccell.2019.12.006
Abstract

Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant Non-Small Cell Lung Cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced Apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced Apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in Cancer patients.

Keywords
YAP; dormancy; drug resistance; drug tolerance; epidermal growth factor receptor; lung cancer; senescence.
Products