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

Kari J Kurppa; Yao Liu; Ciric To; Tinghu Zhang; Mengyang Fan; Amir Vajdi; Erik H Knelson; Yingtian Xie; Klothilda Lim; Paloma Cejas; Andrew Portell; Patrick H Lizotte; Scott B Ficarro; Shuai Li; Ting Chen; Heidi M Haikala; Haiyun Wang; Magda Bahcall; Yang Gao; Sophia Shalhout; Steffen Boettcher; Bo Hee Shin; Tran Thai; Margaret K Wilkens; Michelle L Tillgren; Mierzhati Mushajiang; Man Xu; Jihyun Choi; Arrien A Bertram; Benjamin L Ebert; Rameen Beroukhim; Pratiti Bandopadhayay; Mark M Awad; Prafulla C Gokhale; Paul T Kirschmeier; Jarrod A Marto; Fernando D Camargo; Rizwan Haq; Cloud P Paweletz; Kwok-Kin Wong; David A Barbie; Henry W Long; Nathanael S Gray; Pasi A Jänne

doi:10.1016/j.ccell.2019.12.006

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.

Authors

Kari J Kurppa¹, Yao Liu², Ciric To¹, Tinghu Zhang², Mengyang Fan², Amir Vajdi³, Erik H Knelson¹, Yingtian Xie⁴, Klothilda Lim⁴, Paloma Cejas⁴, Andrew Portell⁵, Patrick H Lizotte⁵, Scott B Ficarro⁶, Shuai Li⁷, Ting Chen⁷, Heidi M Haikala¹, Haiyun Wang⁸, Magda Bahcall¹, Yang Gao⁹, Sophia Shalhout¹⁰, Steffen Boettcher¹¹, Bo Hee Shin¹, Tran Thai¹, Margaret K Wilkens¹², Michelle L Tillgren¹², Mierzhati Mushajiang¹, Man Xu⁵, Jihyun Choi¹, Arrien A Bertram¹, Benjamin L Ebert¹³, Rameen Beroukhim¹⁴, Pratiti Bandopadhayay¹⁵, Mark M Awad¹, Prafulla C Gokhale¹⁶, Paul T Kirschmeier⁵, Jarrod A Marto⁶, Fernando D Camargo¹⁰, Rizwan Haq¹⁷, Cloud P Paweletz⁵, Kwok-Kin Wong⁷, David A Barbie¹, Henry W Long⁴, Nathanael S Gray², Pasi A Jänne¹⁸

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Animals
Apoptosis*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cellular Senescence
Drug Resistance, Neoplasm*
ErbB Receptors / metabolism
Female
Gene Deletion
Gene Expression Regulation, Neoplastic*
Humans
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology
MAP Kinase Kinase 1 / metabolism
Male
Mice
Mice, Knockout
Mutation
Signal Transduction
Transcription Factors / metabolism*
Transcription, Genetic
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
Yap1 protein, mouse
EGFR protein, human
ErbB Receptors
MAP Kinase Kinase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding