2. Academic Validation
  3. Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway

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

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: pasi_janne@dfci.harvard.edu.
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.

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